(2001). "Genetic epidemiology of Creutzfeldt-Jakob disease in Europe." Rev Neurol (Paris) 157(6-7): 633-7.
The prion protein gene was studied in patients with definite or probable Creutzfeldt-Jakob disease (CJD) registered by national CJD units of 6 European countries. The role of genetic factors in CJD was also investigated by comparing the frequencies of a family history of dementia and Parkinson's disease in CJD cases and matched controls. Codon 129 genotype was examined in 337 CJD cases of whom 73.2 p. 100 were homozygous for methionine, 10.9 p. 100 were homozygous for valine and 15.7 p. 100 were heterozygous. The genotype frequencies were not statistically different across countries. Future differences, if any, would constitute a meaningful signal for the surveillance of CJD in Europe. A prion protein gene mutation was found in 14.5 p. 100 of CJD cases; only 40 p. 100 of them had a known family history of CJD. The case-control study showed that positive family histories of dementia and Parkinson's disease were both associated with CJD. Although recall bias is the most likely explanation for this finding, the hypothesis that neurodegenerative diseases might share unknown genetic risk factors can also be considered.

Albers, D. S. and S. J. Augood (2001). "New insights into progressive supranuclear palsy." Trends Neurosci 24(6): 347-53.
Increased oxidative damage and mitochondrial dysfunction have been suggested to play crucial roles in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we will focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with tau pathology. Particular emphasis is placed on the genetic and biochemical data that has emerged, offering new perspectives into the pathogenesis of this devastating disease, especially the contributory roles of oxidative damage and mitochondrial dysfunction.

Andreassen, O. A., R. J. Ferrante, et al. (2001). "Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP." Exp Neurol 167(1): 189-95.
There is substantial evidence implicating mitochondrial dysfunction and free radical generation as major mechanisms of neuronal death in neurodegenerative diseases. The major free radical scavenging enzyme in mitochondria is manganese superoxide dismutase (SOD2). In the present study we investigated the susceptibility of mice with a partial deficiency of SOD2 to the neurotoxins 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate, which are commonly used animal models of Parkinson's and Huntington's disease. Heterozygous SOD2 knockout (SOD2(+/-)) mice showed no evidence of neuropathological or behavioral abnormalities at 2-4 months of age. Compared to littermate wild-type mice, mice with partial SOD2 deficiency showed increased vulnerability to dopamine depletion after systemic MPTP treatment and significantly larger striatal lesions produced by both 3-NP and malonate. SOD2(+/-) mice also showed an increased production of "hydroxyl" radicals after malonate injection measured with the salicylate hydroxyl radical trapping method. These results provide further evidence that reactive oxygen species play an important role in the neurotoxicity of MPTP, malonate, and 3-NP. These findings show that a subclinical deficiency in a free radical scavenging enzyme may act in concert with environmental toxins to produce selective neurodegeneration.

Arvanitakis, Z. and Z. K. Wszolek (2001). "Recent advances in the understanding of tau protein and movement disorders." Curr Opin Neurol 14(4): 491-7.
Tau plays an important role in movement disorders. The accumulation of pathological tau is a major substrate of frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, and corticobasal degeneration. Over the past year, several new mutations on the tau gene have been found. These mutations have been classified into three groups: (i) mutations in constitutively spliced exons; (ii) mutations in the alternatively spliced exon 10; and (iii) mutations of the exon 10 5' splice site. Some patients presenting with frontotemporal dementia and parkinsonism linked to chromosome 17 transiently respond to levodopa therapy. The significance of Pick bodies was recognized by a recent study on kindred with the Glu342Val tau mutation. In sporadic cases of progressive supranuclear palsy, the presence of the H1 haplotype was found to be a risk factor. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. This opens the question of whether corticobasal degeneration represents a separate disorder or a spectrum of disease with progressive supranuclear palsy. However, distinguishing features are observed, and include oculomotor abnormalities, which may help to differentiate these two disorders on clinical grounds. Despite recent advances in the understanding of the tauopathies, there are still no curative therapies available. It is hoped that studies in transgenic tau animal models will lead to the development of successful treatments.

Bandopadhyay, R., R. de Silva, et al. (2001). "No pathogenic mutations in the synphilin-1 gene in Parkinson's disease." Neurosci Lett 307(2): 125-7.
alpha-Synuclein is mutated in rare autosomal dominant forms of Parkinson's disease and is a major component of Lewy bodies and neurites. Synphilin-1, a novel protein interacts in vivo and co-localises with alpha-synuclein in Lewy bodies. We analysed the synphilin-1 gene in familial Parkinson's disease by single-strand conformation polymorphism (SSCP) and automated sequencing but found no coding mutations. However, we identified two novel intronic polymorphisms; an A/T polymorphism in intron 2, resulting in the introduction of an Alu1 site and a second G/T polymorphism in intron 4. We analysed the intron 2 polymorphism for allelic association as it was conducive to rapid screening but observed no changes in frequency between Parkinson's disease cases and controls.

Behari, M., A. K. Srivastava, et al. (2001). "Risk factors of Parkinson's disease in Indian patients." J Neurol Sci 190(1-2): 49-55.
Epidemiological data on risk factors of Parkinson's disease (PD) are not available from India. In a case control study, we investigated environmental and genetic risk factors in the etiology of idiopathic Parkinson's disease. Three hundred seventy-seven patients of Parkinson disease (301 men, 76 women, mean+/-SD age 56.78+/-11.08 years) and equal number of age matched (+/-3 years) neurological controls (271 men, 106 women, mean+/-SD age 56.62+/-11.17 years) were included in the study. Conditional logistic regression model was used to determine the risk factors of PD. We found that male gender, family history of Parkinson's disease, past history of depression of up to 10-year duration and well water drinking of more than 10-year duration were significantly associated with occurrence of Parkinson's disease, whereas tobacco smoking of up to 20-year duration and exposure to pets had protective effect. However, tobacco smoking of more than 20-year duration, well water drinking of up to 10-year duration, vegetarian dietary habit, occupation involving physical exertion, rural living, farming, exposure to insecticides, herbicides, rodenticides, alcohol intake and family history of neurodegenerative diseases had no significant correlation with occurrence of PD in the patient population studied. Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host.

Bertoni, J. M., J. L. Prendes, et al. (2001). "Long-term Medical Treatment for Parkinson's Disease." Curr Treat Options Neurol 3(6): 495-506.
The authors of this paper view Parkinson's disease (PD) as a clinically defined progressive syndrome of resting limb tremor, bradykinesia, muscle rigidity, and a shuffling unsteady gait that responds well to dopaminergic medications. Parkinson's disease is a not a single entity, but rather a syndrome with diverse causes, with both genetic and environmental risk factors. The clinician's concern is to rule out other entities, especially those having another specific treatment, and to give PD patients the best short- and long-term benefit, with the least possible unwanted side effects.

Blair, E., C. Redwood, et al. (2001). "Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis." Hum Mol Genet 10(11): 1215-20.
Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.

Bonifati, V., G. De Michele, et al. (2001). "The parkin gene and its phenotype. Italian PD Genetics Study Group, French PD Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease." Neurol Sci 22(1): 51-2.
Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations.

Bonini, N. M. (2001). "Drosophila as a genetic approach to human neurodegenerative disease." 7(3): 171-175.
Polyglutamine disease is a class of human neurodegenerative diseases characterized by late-onset, progressive neural degeneration. The molecular mechanism is expansion, within the coding region of the respective genes, of a CAG repeat encoding glutamine. The expanded polyglutamine domain confers dominant toxicity on the disease protein, leading to neuronal dysfunction and degeneration. In order to develop Drosophila as a model system to approach and study such human diseases, a human gene encoding an expanded polyglutamine protein was introduced into the fly. Expression of this protein with a pathogenic polyglutamine domain causes late-onset, progressive degeneration of cells in the fly, as it does in humans with disease and mouse transgenic models. Moreover, the protein shows abnormal protein aggregation in flies, similar to human disease tissue. These studies indicate that molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila. Through these studies and additional studies to develop fly models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular understanding and treatment of human neurodegeneration.

Bostantjopoulou, S., Z. Katsarou, et al. (2001). "Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation." Mov Disord 16(6): 1007-1013.
The motor and neuropsychological abnormalities in eight Greek patients with Parkinson's disease (PD) carrying the alpha-synuclein gene mutation (G209A) were studied. These patients (five men, three women) belonged to six different families. Their symptoms started between 32-50 years of age (mean +/- SD, 39.7 +/- 7.6 years) and they had a mean disease duration of 5.4 +/- 2.1 years (range, 2-9 years) at the time of examination. Rigidity and bradykinesia predominated both at disease onset as well as in the later stages and rest tremor was relatively uncommon. Neuropsychological assessment showed that one patient was mildly demented while another had impairment in memory, visuoconstructive abilities, and executive function. Depression was present in only one patient. Our findings indicate that genetic forms of parkinsonism share common motor and cognitive characteristics with sporadic PD but raise the possibility that greater cognitive impairment and the relative rarity of tremor may be distinctive features worthy of further investigation. Copyright 2001 Movement Disorder Society.

Cadet, J. L. (2001). "Molecular neurotoxicological models of Parkinsonism: focus on genetic manipulation of mice." 8(2): 85-90.
Parkinson's disease is a neurodegenerative disorder that affects mainly the nigrostriatal dopaminergic system in humans. Several propositions have been put forward to explain the cellular and molecular pathobiology of this syndrome. Initial attempts were made through the use of various agents to manipulate the deleterious effects of toxins that destroy dopaminergic cells both in vitro and in vivo. These studies led to the idea that oxidative stress is an important factor in killing these cells. More recent attempts have made use of genetically modified mice to eliminate or over-express genes of interest. These experiments have suggested that the destruction of dopaminergic cells might be the result of the convergence of dependent and independent molecular pathways and that trigger cellular events might lead to the demise of these dopaminergic cells.

Chen, C. H., C. C. Hung, et al. (2001). "Debrisoquine 4-hydroxylase (CYP2D6) genetic polymorphisms and susceptibility to schizophrenia in Chinese patients from Taiwan." Psychiatr Genet 11(3): 153-5.
Debrisoquine 4-hydroxylase (CYP2D6) is one of the cytochrome P450 enzyme families that metabolize many compounds. Polymorphic activities of debrisoquine 4-hydroxylase were suggested to be associated with some complex diseases, such as cancer and Parkinson's disease. Schizophrenia is also a complex disorder, and hence we are interested in understanding if the CYP2D6 gene is a susceptibility gene for schizophrenia in Chinese. We determined the genotype and allele frequencies of four molecular variants of CYP2D6 gene (i.e. 188C/T, 1934G/A, 2938C/T and 4268C/G) in 162 Chinese schizophrenic patients and 94 non-psychotic control subjects from Taiwan. No significant differences of allele or genotype frequencies of three polymorphisms (i.e. 188T/C, 2938C/T and 4268C/G) were detected between patients and control subjects. The 1934A allele, which accounts for the majority of poor metabolizers in Caucasians, was not detected in either patients or control subjects, indicating that the 1934A allele is very rare in Chinese. Our data suggest that the CYP2D6 gene may not be a susceptibility gene for schizophrenia in Chinese schizophrenic patients.

Chen, J. F., K. Xu, et al. (2001). "Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease." J Neurosci 21(10): RC143.
Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5 -c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.

Cole, N. B., D. D. Murphy, et al. (2001). "Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein." J Biol Chem.
alpha-Synuclein is a major component of the fibrillary lesion known as Lewy bodies (LBs) and Lewy neurites (LNs) that are the pathologic hallmarks of Parkinson's disease (PD). In addition, point mutations in the alpha-synuclein gene implicate alpha-synuclein dysfunction in the pathology of inherited forms of PD. alpha-Synuclein is a member of a family of proteins found primarily in the brain and is concentrated within presynaptic terminals. Here, we address the localization and membrane binding characteristics of wild type and PD mutants of alpha synuclein in cultured cells. In cells treated with high concentrations of fatty acids, wild type alpha-synuclein accumulated on phospholipid monolayers surrounding triglyceride-rich lipid droplets, and was able to protect stored triglycerides from hydrolysis. PD mutant synucleins showed variable distributions on lipid droplets and were less effective in regulating triglyceride turnover. Chemical crosslinking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes. Our results suggest that the initial phases of synuclein aggregation may occur on the surfaces of membranes, and that pathological conditions that induce crosslinking of synuclein may enhance the propensity for subsequent synuclein aggregation.

Connor, B., D. A. Kozlowski, et al. (2001). "Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration." Exp Neurol 169(1): 83-95.
Previously, we observed that injection of an adenoviral (Ad) vector expressing glial cell line-derived neurotrophic factor (GDNF) into the striatum, but not the substantia nigra (SN), prior to a partial 6-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavioral impairment in the aged rat. This suggests that striatal injection of AdGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum. To distinguish between these possible mechanisms, the present study examines the effect of GDNF gene delivery on molecular markers of DA terminals and neuronal sprouting in the aged (20 month) rat brain. AdGDNF or a control vector coding for beta-galactosidase (AdLacZ) was injected unilaterally into either the striatum or the SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the side of vector injection. Two weeks postlesion, rats injected with AdGDNF into either the striatum or the SN exhibited a reduction in the area of striatal denervation and increased binding of the DA transporter ligand [(125)I]IPCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDNF into the striatum, but not the SN, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asymmetry. In contrast, the level of T1 alpha-tubulin mRNA, a marker of neuronal sprouting, was not increased in lesioned DA neurons in the SN following injection of AdGDNF either into the striatum or into the SN. These results suggest that GDNF gene delivery prior to a partial lesion ameliorates damage caused by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals rather than by inducing sprouting of nigrostriatal axons. Copyright 2001 Academic Press.

Crocker, S. J., N. Wigle, et al. (2001). "NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-OHDA rat model of Parkinson's disease." Eur J Neurosci 14(2): 391-400.
Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.

Date, I., T. Shingo, et al. (2001). "Grafting of encapsulated genetically modified cells secreting GDNF into the striatum of parkinsonian model rats." Cell Transplant 10(4-5): 397-401.
In order to deliver glial cell line-derived neurotrophic factor (GDNF) into the brain, we have established a cell line that produces GDNF in a continuous fashion by genetic engineering. These cells were encapsulated and grafted into parkinsonian model rats that had received unilateral intrastriatal injection of 6-hydroxydopamine 2 weeks earlier. Neurochemical analysis showed that GDNF has been produced from the capsule for 6 months after grafting and histological analysis revealed good survival of GDNF-producing cells in the capsule 6 months after grafting. The density of nigrostriatal dopaminergic fibers in the striatum as well as the number of dopaminergic cell bodies in the substantia nigra recovered significantly after GDNF-producing cell grafting. These results suggest the possible application of GDNF-producing cell grafting for the treatment of Parkinson's disease.

DeStefano, A. L., L. I. Golbe, et al. (2001). "Genome-wide scan for Parkinson's disease: the GenePD Study." Neurology 57(6): 1124-6.
A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Doevendans, P. A. and H. J. Wellens (2001). "Wolff-Parkinson-White Syndrome: A Genetic Disease?" Circulation 104(25): 3014-3016.

Dujardin, K., L. Defebvre, et al. (2001). "Memory and executive function in sporadic and familial Parkinson's disease." Brain 124(Pt 2): 389-98.
Some studies have demonstrated that the motor symptomatology in sporadic and familial Parkinson's disease was identical. From a physiopathological point of view, and perhaps in the future from a therapeutic point of view, it seems important to determine whether sporadic and familial Parkinson's disease are also similar with regard to cognitive impairment. The aim of the present study was to assess cognitive functions in patients suffering from sporadic and familial Parkinson's disease. Executive functions and memory were investigated in particular. Two groups of 12 patients with Parkinson's disease (sporadic and familial) and 12 healthy controls performed a set of tasks known to evaluate different aspects of executive function and memory. One-way analysis of variance tested for significant group effects, and when justified, post hoc analysis was performed. Cognitive impairment was different in sporadic and familial forms of Parkinson's disease. Indeed, although executive function was impaired in both groups of patients, deficits in tests of explicit memory recall were only observed in patients with sporadic Parkinson's disease. Although the impairment observed in both groups of patients suggests a disruption of the striatoprefrontal circuits, this disruption seems to be quantitatively more important and more widespread in the sporadic patients than in the familial ones. In both patient groups, the deficits probably result from dopaminergic and nondopaminergic deprivation and a greater participation of nondopaminergic factors in patients with sporadic Parkinson's disease could be suggested. In this group, a xenobiotic could be responsible for an acquired metabolic defect involving more widespread structures of the striatoprefrontal circuits, leading to disruption of nondopaminergic loops. Cholinergic deprivation is considered in particular.

During, M. J., M. G. Kaplitt, et al. (2001). "Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation." Hum Gene Ther 12(12): 1589-91.
This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.

Ebadi, M., P. Govitrapong, et al. (2001). "Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease." Biol Signals Recept 10(3-4): 224-53.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.

Ellis, C. E., P. L. Schwartzberg, et al. (2001). "alpha-synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases." J Biol Chem 276(6): 3879-84.
alpha-Synuclein (alpha-Syn) is implicated in the pathogenesis of Parkinson's Disease, genetically through missense mutations linked to early onset disease and pathologically through its presence in Lewy bodies. alpha-Syn is phosphorylated on serine residues; however, tyrosine phosphorylation of alpha-Syn has not been established (, ). A comparison of the protein sequence between Synuclein family members revealed that all four tyrosine residues of alpha-Syn are conserved in all orthologs and beta-Syn paralogs described to date, suggesting that these residues may be of functional importance (). For this reason, experiments were performed to determine whether alpha-Syn could be phosphorylated on tyrosine residue(s) in human cells. Indeed, alpha-Syn is phosphorylated within 2 min of pervanadate treatment in alpha-Syn-transfected cells. Tyrosine phosphorylation occurs primarily on tyrosine 125 and was inhibited by PP2, a selective inhibitor of Src protein-tyrosine kinase (PTK) family members at concentrations consistent with inhibition of Src function (). Finally, we demonstrate that alpha-Syn can be phosphorylated directly both in cotransfection experiments using c-Src and Fyn expression vectors and in in vitro kinase assays with purified kinases. These data suggest that alpha-Syn can be a target for phosphorylation by the Src family of PTKs.

Emborg, M. E., P. Shin, et al. (2001). "Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys." Exp Neurol 168(1): 171-82.
Systemic administration of immunophilin ligands provides trophic influences to dopaminergic neurons in rodent models of Parkinson's disease (PD) resulting in the initiation of clinical trials in patients with Parkinson's disease. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present study assessed whether oral administration of the immunophilin 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GPI 1046) could prevent the structural and functional consequences of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman primates. Twenty-five rhesus monkeys received daily oral administration of vehicle (n = 5) or one of four doses of GPI 1046 (0.3 mg/kg, n = 5; 1.0 mg/kg, n = 5; 3.0 mg/kg, n = 5; 10.0 mg/kg, n = 5). Two weeks after starting the drug treatment, all monkeys received a unilateral intracarotid injection of MPTP-HCl (3 mg). Daily drug administration continue for 6 weeks postlesion after which time the monkeys were sacrificed. Monkeys were assessed for performance on a hand reach task, general activity, and clinical dysfunction based on a clinical rating scale. All groups of monkeys displayed similar deficits on each behavioral measure as well as similar losses of tyrosine hydroxylase (TH)-immunoreactive (ir) nigral neurons, TH-mRNA, and TH-ir striatal optical density indicating that in general treatment failed to have neuroprotective effects. Copyright 2001 Academic Press.

Farin, F. M., Y. Hitosis, et al. (2001). "Genetic polymorphisms of superoxide dismutase in Parkinson's disease." Mov Disord 16(4): 705-7.
Oxidative stress reactions may contribute to the pathogenesis of Parkinson's disease (PD). The superoxide dismutases potentially play significant roles in PD by detoxifying superoxide radical. We developed genomic DNA and cDNA-based sequencing assays to identify genetic variants in the copper/zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes. No genetic variants were detected in the gene encoding SOD1 in DNA from 45 idiopathic PD cases and 49 controls from a population-based case-control study. However, we identified a previously described polymorphism of the mitochondrial targeting sequence consisting of a C47T in exon 2 of SOD2, which results in an alanine to valine substitution. We analyzed this SOD2 variant in DNA from 155 cases and 231 controls from the same study, using an allele-specific fluorogenic 5' nuclease assay, and found no differences in the distributions of allelic frequencies. These results indicate that SOD gene variants do not contribute to PD pathogenesis.

Farin, F. M., P. Janssen, et al. (2001). "Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease." Pharmacogenetics 11(8): 703-8.
Oxidative stress is hypothesized to play a major role in the destruction of dopaminergic neurons, which is associated with Parkinson's disease. Epoxides are potentially reactive intermediates formed through the oxidative metabolism of both exogenous and endogenous substances that contribute to cytotoxic damage mediated by oxidative stress. The microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases function to regulate the oxidation status of a wide range of xenobiotic- and lipid-derived substrates; therefore, interindividual variation in these pathways may mitigate epoxide-related cellular injury. In this investigation, we examined the potential association between the risk of Parkinson's disease and genetic variation within the EPHX1 and EPHX2 genes. Fluorescent 5' nuclease-based assays were developed to identify the allelic status of individuals with respect to specific single nucleotide polymorphisms in exons 3 and 4 of the EPHX1 gene and exons 8 and 13 of the EPHX2 gene. EPHX1 and EPHX2 genotype data were obtained from 133 idiopathic Parkinson's disease patients and 212 control subjects matched on age, gender and ethnicity. No statistically significant differences were found in the distribution of the reference and variant alleles between Parkinson's disease and control subjects, or when results were stratified by gender. Therefore, common polymorphisms within EPHX1 and EPHX2 do not appear to be important risk factors for Parkinson's disease.

Farrer, M., P. Chan, et al. (2001). "Lewy bodies and parkinsonism in families with parkin mutations." Ann Neurol 50(3): 293-300.
Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early-onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early-onset Parkinson's disease (Ê41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2-27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early-onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.

Farrer, M., A. Destee, et al. (2001). "Genetic analysis of synphilin-1 in familial Parkinson's disease." Neurobiol Dis 8(2): 317-23.
alpha-Synuclein is present in Lewy bodies of patients with both sporadic and familial Parkinson's disease. However, pathogenic mutations Ala30Pro and Ala53Thr in alpha-synuclein are rare causes of disease. Synphilin-1 has been demonstrated to associate with alpha-synuclein and promote the formation of cytosolic inclusions in vitro. Two-point genetic linkage analysis of a dinucleotide repeat within the synphilin-1 gene initially implicated this locus as a cause of Parkinson's disease in three of nine families. However, subsequent haplotype, sequencing, and association analyses in these three families and an independent case-control series suggest that variability within the locus does not confer susceptibility to Parkinson's disease. Copyright 2001 Academic Press.

Farrer, M., D. M. Maraganore, et al. (2001). "alpha-Synuclein gene haplotypes are associated with Parkinson's disease." Hum Mol Genet 10(17): 1847-51.
We report haplotype analysis of the alpha-synuclein gene in Parkinson's disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and controls. Our analyses demonstrate that genetic variability in the alpha-synuclein gene is a risk factor for the development of PD. These genetic findings are analogous to the tau haplotype over-represented in progressive supranuclear palsy and further extend the similarity in the etiologies and pathogeneses of the synucleinopathies and tauopathies.

Ferrarese, C., L. Tremolizzo, et al. (2001). "Decreased platelet glutamate uptake and genetic risk factors in patients with Parkinson's disease." Neurol Sci 22(1): 65-6.
Genetic risk factors seem to play a role in sporadic Parkinson's disease (PD), maybe triggering oxidative stress and excitotoxicity within substantia nigra. However, genetic factors act at systemic level: reduced activity of mitochondrial enzymes and decreased glutamate uptake have been shown in platelets from PD patients. In this study we investigated glutamate uptake in platelets from 38 sporadic PD patients, 13 patients with parkinsonian syndromes and 28 controls and assessed polymorphisms of alpha-synuclein and ApoE genes. A 48% reduction of glutamate uptake p)<0.0001) was observed in PD patients which, with respect to control groups, correlated with the disease severity (r = -0.44, p < 0.05). Genetic studies of this population did not show differences between PD and controls, nor correlations with platelet glutamate uptake.

Forsberg, L., U. de Faire, et al. (2001). "Oxidative stress, human genetic variation, and disease." Arch Biochem Biophys 389(1): 84-93.
Oxidative stress has been implicated in numerous pathophysiological conditions and also aging. The tools for studying oxidative stress are now expanding as a result of the human genome effort and, in particular, expanding knowledge on human genetic variation. A few genetic variants, mostly in the form of single nucleotide polymorphisms of relevance to oxidative stress are already studied by a molecular epidemiologic approach. A review of the current knowledge on variant human genes that are directly implicated in human protection against oxidative stress is presented.

Fukui, T., Y. Hayashi, et al. (2001). "Suicide gene therapy for human oral squamous cell carcinoma cell lines with adeno-associated virus vector." Oral Oncol 37(3): 211-5.
The purpose of this study was to test the possibility of gene transfer as a new therapy for oral cancer. Adeno-associated virus (AAV) has already been used in the fields of cystic fibrosis and Parkinson's disease as a potential vector for gene therapy because of its wide host range, high transduction efficiency, and lack of cytopathogenicity. Four human oral squamous cell carcinoma cell lines were transduced with an AAV vector containing the beta-galactosidase gene (AAVlacZ) in vitro. Gene transduction efficiency was from 20 to 50% at a multiplicity of infection (MOI; for the purposes of this study the number of vector genomes per target cell) of 1x10(3), and nearly 100% of each cell line were transduced at an MOI of 1x10(4). Next, four cell lines were transduced with an AAV vector containing the herpes simplex virus thymidine kinase (HSVtk) gene, which sensitizes transduced cells to ganciclovir (GCV). Subsequent administration of GCV resulted in nearly 100% tumor cell killing at an MOI of 1x10(4) and from 70 to 80% tumor cell killing at an MOI of 1x10(3). These results suggest that AAV-mediated gene transfer of HSVtk and administration of GCV has potential as a new therapy for oral squamous cell carcinoma.

Gasser, T. (2001). "Genetics of Parkinson's disease." J Neurol 248(10): 833-40.
Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Gerlai, R., A. McNamara, et al. (2001). "Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation." Eur J Neurosci 14(7): 1153-63.
Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities.

Giasson, B. I. and V. M. Lee (2001). "Parkin and the molecular pathways of parkinson's disease." Neuron 31(6): 885-8.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective demise of specific neuronal populations leading to impairment of motor functions. Recent genetic studies have uncovered several genes involved in inherited forms of the disease. These gene products are implicated in the biochemical pathways underlying the etiology of sporadic PD. Mutations in the parkin gene causal of autosomal recessive juvenile parkinsonism highlight that ubiquitin-mediated proteolysis may play an important role in the pathobiology of PD.

Goedert, M. (2001). "Parkinson's disease and other alpha-synucleinopathies." Clin Chem Lab Med 39(4): 308-12.
Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene and that the filamentous lesions of Parkinson's disease are made of alpha-synuclein. The same is true of the Lewy body pathology that is associated with other neurodegenerative diseases, such as dementia with Lewy bodies. The filamentous inclusions of multiple system atrophy have also been found to be made of alpha-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant alpha-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-beta diffraction pattern characteristic of amyloid. The related proteins beta-synuclein and gamma-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease.

Goetz, C. G., P. F. Burke, et al. (2001). "Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study." Arch Neurol 58(2): 209-13.
BACKGROUND: Visual hallucinations in Parkinson disease (PD) occur in approximately one third of patients treated long-term with dopaminergic medications. In Alzheimer disease, hallucinations and psychosis have been linked to increased representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without hallucinations did not show differences in D2 and D3 polymorphisms, although careful case-control matching was not performed. Another study linked the apolipoprotein E4 (APOE4) allele to hallucinations in PD. OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease. METHODS: We conducted a case-control study of 44 patients with PD and chronic hallucinations and 44 patients with PD who had never hallucinated. Cases and controls were matched for current age and medications. DNA was isolated from blood samples and assayed for DRD1, DRD2, DRD3, DRD4, and APOE polymorphisms. Receptor polymorphisms were genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies were compared using Wilcoxon signed rank tests within pairs. RESULTS: Neither D1 receptor genotypes (P =.37) nor allele frequencies (P =.38) differed, and there was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there was a higher frequency of allele 2 (P =.047), but there was no significant difference between frequencies of homozygotes vs heterozygotes (P =.39) as reported in Alzheimer disease. D4 receptor distribution of long and short alleles did not differ between the 2 patient groups, and there were too few C alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99). CONCLUSIONS: With careful case-control matching, visual hallucinations in PD are not associated with the pattern seen for patients with Alzheimer disease and visual hallucinations. Furthermore, there was no association between hallucinations and APOE. Similar methods using larger sample sizes might be adapted to test whether specific dopaminergic receptor genetic variants are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.

Golbe, L. I., A. M. Lazzarini, et al. (2001). "The tau A0 allele in Parkinson's disease." Mov Disord 16(3): 442-7.
Parkinson's disease (PD) is primarily an alpha-synucleinopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis. Copyright 2001 Movement Disorder Society.

Gollob, M. H., M. S. Green, et al. (2001). "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome." N Engl J Med 344(24): 1823-31.
BACKGROUND: The Wolff-Parkinson-White syndrome, with a prevalence in Western countries of 1.5 to 3.1 per 1000 persons, causes considerable morbidity and may cause sudden death. We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder. METHODS: We studied 70 members of the two families (57 in Family 1 and 13 in Family 2). The subjects underwent 12-lead electrocardiography and two-dimensional echocardiography. Genotyping mapped the gene responsible to 7q34-q36, a locus previously identified to be responsible for an inherited form of Wolff-Parkinson-White syndrome. Candidate genes were identified, sequenced, and analyzed in normal and affected family members to identify the disease-causing gene. RESULTS: A total of 31 members (23 from Family 1 and 8 from Family 2) had the Wolff-Parkinson-White syndrome. Affected members of both families had ventricular preexcitation with conduction abnormalities and cardiac hypertrophy. The maximal combined two-point lod score was 9.82 at a distance of 5 cM from marker D7S636, which confirmed the linkage of the gene in both families to 7q34-q36. Haplotype analysis indicated that there were no alleles in common in the two families at this locus, suggesting that the two families do not have a common founder. We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. CONCLUSIONS: The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.

Gollob, M. H., J. J. Seger, et al. (2001). "Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy." Circulation 104(25): 3030-3033.
BACKGROUND: We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results- DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. CONCLUSIONS: We identified a novel mutation (Arg531Gly) in the gamma-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease. These observations confirm an important functional role of AMPK in the regulation of ion channels specific to cardiac tissue. The identification of the cardiac ion channel(s) serving as substrate for AMPK not only would provide insight into the molecular basis of atrial fibrillation and heart block but also may suggest targets for the development of more specific therapy for these common rhythm disturbances.

Gulcher, J. R., A. Kong, et al. (2001). "The role of linkage studies for common diseases." Curr Opin Genet Dev 11(3): 264-7.
Linkage analysis when applied to common diseases has had limited success in mapping the genes contributing to them. We present a genealogic approach applied to the relatively isolated population of Iceland. We use an affecteds-only, allele-sharing method--which does not specify any particular inheritance model--implemented in the new statistical program, Allegro, which calculates lod scores based on multipoint calculations. We describe how this approach has helped us to map a gene contributing to the common late-onset form of Parkinson's disease to statistical significance.

Gwinn-Hardy, K., A. Singleton, et al. (2001). "Spinocerebellar ataxia type 3 phenotypically resembling parkinson disease in a black family." Arch Neurol 58(2): 296-9.
BACKGROUND: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), can present with parkinsonism. However, classically, atypical features, including pyramidal and cerebellar signs, peripheral neuropathy, and/or anterior horn cell dysfunction, are also seen. Levodopa responsiveness is unusual in this disorder. OBJECTIVE: To determine the cause of apparent parkinsonism suggestive of Parkinson disease (PD) in a large family of African origin. METHODS: We studied a large family in which apparent autosomal dominant parkinsonism suggestive of PD occurs in order to find the causal genetic mutation. Affected and unaffected family members were screened for the presence of a pathogenic expansion at the MJD/SCA3 locus using a polymerase chain reaction polyacrylamide gel electrophoresis-based assay. RESULTS: Three of the 4 individuals who were examined have a phenotype reminiscent of PD. Specifically, they have at least 2 of the cardinal features, are levodopa responsive, and have no atypical features. All affected family members were shown to possess pathogenic expansions in the MJD/SCA3 gene. CONCLUSIONS: Parkinsonism suggestive of PD due to MJD/SCA3 has not been previously reported, to our knowledge. However, atypical, though also levodopa-responsive, parkinsonism has been previously reported to occur in African American families, suggesting that that this phenotype is associated with African ancestry. In this regard, it is perhaps significant that all the individuals with parkinsonism have relatively low numbers of repeats (normal, 16-34; pathologic, 60-84). In families in which linkage analysis is being performed to determine a locus for autosomal dominant parkinsonism suggestive of PD, evaluation for the MJD/SCA3 mutation is indicated.

Henderson, J. M., W. P. Gai, et al. (2001). "Parkinson's disease with late Pick's dementia." Mov Disord 16(2): 311-9.
We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause. Copyright 2001 Movement Disorder Society.

Hofele, K., M. Sedelis, et al. (2001). "Evidence for a dissociation between MPTP toxicity and tyrosinase activity based on congenic mouse strain susceptibility." Exp Neurol 168(1): 116-22.
The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable available models for investigating critical aspects of human Parkinson's disease. In order to analyze the relevance of pigmentation for MPTP sensitivity, we compared C57Bl/6 wild-type mice with the albino mutant C57Bl/6J-Tyr(c-2J) of the same strain. These animals were treated either with systemic MPTP or with saline and were examined in behavioral tests. Seven days after treatment, the contents of dopamine and other monoamines were determined postmortem in the neostriatum and ventral striatum. Furthermore, the numbers of tyrosine hydroxylase-positive cells were counted in the substantia nigra and ventral tegmental area. Open field testing showed that rearing activity was drastically reduced as an acute effect of MPTP in both wild type and mutants; however, subsequent recovery to control levels was faster in wild-type mice. Nest building also indicated strain-dependent effects, since it was delayed only in mutants treated with MPTP. Neurochemically, MPTP led to severe neostriatal dopamine depletions, which did not differ significantly between wild-type (72.9%) and mutant mice (82.1%). Less severe dopamine depletions were also found in the ventral striatum. Histologically, a loss of tyrosine hydroxylase-labeled cells was observed only in the substantia nigra of both wild-type and mutant mice (13.3 and 21.3%, respectively), but not in the ventral tegmental area. Together, our data do not provide evidence that tyrosinase-deficient mice are less affected by MPTP treatment than the comparable wild type, thus arguing strongly against the hypothesis that enhanced MPTP sensitivity in pigmented mouse strains is caused by tyrosinase activity. Copyright 2001 Academic Press.

Holm, K. H., F. Cicchetti, et al. (2001). "Enhanced axonal growth from fetal human bcl-2 transgenic mouse dopamine neurons transplanted to the adult rat striatum." Neuroscience 104(2): 397-405.
Embryonic neurons transplanted to the adult CNS extend axons only for a developmentally defined period. There are certain intercellular factors that control the axonal extension, one of which may be the expression of the bcl-2 protein. In this study, rats with complete striatal dopamine fiber denervation received embryonic day 14 mouse ventral mesencephalon cells overexpressing human bcl-2 or control wild-type ventral mesencephalon cells. All rats were treated with cyclosporine to prevent rejection and the surviving grafts were analyzed for cell survival and outgrowth of dopaminergic fibers. The results demonstrate that bcl-2 overexpression does not enhance neuronal graft survival. However, the bcl-2 overexpressing neurons had a higher number of dopaminergic fibers that grew longer distances.These results show that overexpression of bcl-2 can result in longer distance axonal growth of transplanted fetal dopaminergic neurons and that genetic modification of embryonic donor cells may enhance their ability to reinnervate a neuronal target territory.

Ingelson, M., S. F. Fabre, et al. (2001). "Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4." Neuroreport 12(5): 905-9.
The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.

Izumi, Y., H. Morino, et al. (2001). "Genetic studies in Parkinson's disease with an alpha-synuclein/NACP gene polymorphism in Japan." Neurosci Lett 300(2): 125-7.
Dinucleotide repeat polymorphism has been observed in the promoter of the alpha-synuclein (alpha-SYN)/NAC precursor protein (NACP) gene. Alpha-SYN/NACP allele 3 (described by Xia et al. (Ann. Neurol., 40 (1996) 207), equivalent to allele 1 described by Kruger et al. (Ann. Neurol. 45 (1999) 611) is reported to be significantly more frequent among patients with sporadic Parkinson's disease (sPD) than controls. In this study, we genotyped the same alpha-SYN/NACP polymorphism in Japanese sPD patients and healthy controls, but found that any aliele showed no significant difference between the two groups.

Jacobs, H., U. Latza, et al. (2001). "Attitudes of young patients with Parkinson's disease towards possible presymptomatic and prenatal genetic testing." Genet Couns 12(1): 55-67.
OBJECTIVE: To evaluate the opinions and attitudes of young patients with Parkinson's disease (PD) towards possible presymptomatic and prenatal genetic testing for their illness. Background: With progress in understanding of the genetic component in the etiology of PD, presymptomatic genetic testing may become available in subgroups of patients. METHODS: During a survey on sociodemographic and risk factors 111 PD patients (mean age 45 years: mean age at PD onset 36 years) were given a questionnaire with six items about possible presymptomatic and prenatal genetic testing. RESULTS: Fifty-seven patients (5196) had knowledge about presymptomatic and prenatal testing. Eighty patients (72%) would take a presymptomatic test, if they had an autosomal dominant form of PD and if the test were available. The most Important reasons given for taking the test were planning of partnership (40%) and family (48%). When being identified as a carrier of a presumed "Parkinson gene", 78 patients (70%) would decide not to have children. Sixty-three patients (57%) would choose to have prenatal testing. Attitudes were largely independent of sociodemographic and disease variables. CONCLUSIONS: When addressed as hypothetical persons at genetic risk, young patients with PD support possible presymptomatic genetic testing and, to a lesser extent, prenatal testing. Attitudes and reasons to participate in such hypothetical testing do not grossly differ from those of at-risk persons in established single-gene autosomal dominant disorders of late onset.

Jankovic, J. and R. Tintner (2001). "Dystonia and parkinsonism." 8(2): 109-121.
Parkinsonism and dystonia may coexist in a number of neurodegenerative, genetic, toxic, and metabolic disorders and as a result of structural lesions in the basal ganglia. Parkinson's disease (PD) and the 'Parkinson-plus' syndromes (PPS) account for the majority of patients with the parkinsonism-dystonia combination. Dystonia, particularly when it involves the foot, may be the presenting sign of PD or PPS and these disorders should be suspected when adults present with isolated foot dystonia. Young age, female gender, and long disease duration are risk factors for PD-related dystonia, but dystonia in patients with PD is usually related to levodopa therapy. The mechanism of dystonia in PD is not well understood and the management is often challenging because levodopa and other dopaminergic agents may either improve or worsen dystonia. Other therapeutic strategies include oral medications (baclofen, anticholinergics and benzodiazepines), local injections of botulinum toxin, intrathecal baclofen, and surgical lesions or high frequency stimulation of the thalamus, globus pallidus, or subthalamus.

Jeon, B. S., J. M. Kim, et al. (2001). "An apparently sporadic case with parkin gene mutation in a Korean woman." Arch Neurol 58(6): 988-9.
OBJECTIVE: To report the clinical features and results of iodine I 123-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane (CIT) single photon emission computed tomography and molecular genetic analysis in a Korean woman with juvenile Parkinson disease with deletion in exon 4 of the parkin gene. DESIGN: Case report with molecular genetic analysis. PATIENT AND RESULTS: The patient had bradykinesia, postural imbalance, and postural tremor since the age of 12 years. She developed wearing off early in the disease course. The [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography showed severe reduction of specific striatal CIT binding, comparable to that of Parkinson disease. The polymerase chain reaction products from the parkin gene showed homozygous exon 4 deletion. CONCLUSION: In this sporadic juvenile Parkinson disease case, severe nigrostriatal dopaminergic damage and homozygous exon 4 deletion in the parkin gene were demonstrated.

Khan, N., E. Graham, et al. (2001). "Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype." Ann Neurol 49(5): 665-8.
A recent study showed significant association of sporadic Parkinson's disease with a polymorphism within the alpha-synuclein gene and closely linked DNA markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha-synuclein/APOE-epsilon4 genotype increased the relative risk of developing Parkinson's disease 12-fold. We failed to confirm this association in a much larger sample of histopathologically proven cases of Parkinson's disease and controls.

Klein, C. (2001). "[The genetics of Parkinson syndrome]." Schweiz Rundsch Med Prax 90(23): 1015-23.
A genetic contribution to the etiology of Parkinson's disease was first suspected by Charcot and later confirmed by case control, family, and twin studies, as well as by the description of large parkinsonian families with Mendelian inheritance of the disease. Recent progress in the field of molecular neurogenetics has led to the identification of several Parkinson disease genes and gene loci. Mutations in the alpha-Synuclein gene (PARK1) and in the gene for the ubiquitin C-terminal hydrolase I (PARK5), along with two gene loci harboring currently unknown genes (PARK3 and PARK4), have been linked to very rare autosomal dominantly inherited parkinsonian syndromes. Mutations in the parkins gene (PARK2), causing autosomal recessive early-onset parkinsonism, are much more common and therefore of clinical relevance. A second gene locus for an autosomal dominantly inherited Parkinsonian syndrome was recently localized on chromosome 1 (PARK6). All three parkinson genes identified thus far imply the involvement of the ubiquitin pathway of protein degradation in the pathogenesis of Parkinson's disease.

Kuopio, A., R. J. Marttila, et al. (2001). "Familial occurrence of Parkinson's disease in a community-based case-control study." 7(4): 297-303.
Purpose: To study the occurrence of Parkinson's disease (PD) in the relatives of parkinsonian patients (n=119), and of their matched controls (n=238).Scope: More patients reported a positive family history of PD in their first degree relatives, compared to their controls (OR 2.7, 95% CI 1.3-5.9), and the incidence of PD among those relatives was also significantly higher (OR 1.4, 95% CI 1.1-1.8).Conclusions: Familial occurrence of PD is not necessarily a sign of genetic mechanisms in the etiology of PD. Shared environment with common risk factors might be even more important.

Laing, N. (2001). "Genes and brains, molecular medicine and neuropathology." Trends Mol Med 7(1): 6-7.

Latchman, D. S. and R. S. Coffin (2001). "Viral vectors for gene therapy in Parkinson's disease." Rev Neurosci 12(1): 69-78.
The ability of transplanted neurons from aborted foetuses to produce some therapeutic benefit in Parkinson's disease makes this disease an obvious target for the development of gene therapy procedures which involve delivering the same factors as are provided by the foetal neurons but using a reagent which could be produced in large amounts in a standardised manner. This approach could involve both the delivery of the gene encoding tyrosine hydroxylase to boost dopamine production or the delivery of genes encoding neurotrophic factors such as GDNF to promote the survival of dopaminergic neurons. A variety of different viral and non-viral methods for achieving such gene delivery has been described. These are discussed together with the particular advantages of herpes simplex virus-based vectors which have the potential to deliver multiple therapeutic genes in a single virus vector.

Layfield, R., A. Alban, et al. (2001). "The ubiquitin protein catabolic disorders." Neuropathol Appl Neurobiol 27(3): 171-9.
The ubiquitin-proteasome system of intracellular proteolysis is essential for cell viability. We propose the concept that neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other conditions including some types of cancer, collectively represent a raft of 'ubiquitin protein catabolic disorders' in which altered function of the ubiquitin-proteasome system can cause or directly contribute to disease pathogenesis. Genetic abnormalities within the ubiquitin pathway, either in ubiquitin-ligase (E3) enzymes or in deubiquitinating enzymes, cause disease because of problems associated with substrate recognition or supply of free ubiquitin, respectively. In some cases, mutations in protein substrates of the ubiquitin-proteasome system may directly contribute to disease progression because of inefficient substrate recognition. Mutations in transcripts for the ubiquitin protein itself (as a result of 'molecular misreading') also affect ubiquitin-dependent proteolysis with catastrophic consequences. This has been shown in Alzheimer's disease and could apply to other age-associated neurodegenerative conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin-dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases.

Lee, M. S., C. H. Lyoo, et al. (2001). "Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease." Neurosci Lett 298(2): 131-4.
A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high and low activity forms of the enzyme. We investigated COMT genotypes of 73 Korean patients with Parkinson's disease (PD), 29 with multiple system atrophy (MSA), and 49 controls, and analyzed the response to levodopa challenge in the PD patients. We found no significant difference in the distribution of the COMT genotypes among the three groups. The frequencies of the G- and A-alleles in the total population were 75 and 25%, respectively. The levodopa response was determined by a single oral levodopa challenge test with Sinemet (25/250 mg) in the patients with PD. The motor response evaluated by the time to peak response, the duration and magnitude of the response in the motor part of the Unified Parkinson's Disease Rating Scale; tapping or walking times showed no significant difference between the genotypes. Thus, pharmacokinetic or pharmacodynamic factors other than the investigated genetic variant of the COMT enzyme seem to determine the response to levodopa in PD.

Leenders, K. L. and W. H. Oertel (2001). "Parkinson's disease: clinical signs and symptoms, neural mechanisms, positron emission tomography, and therapeutic interventions." Neural Plast 8(1-2): 99-110.
Parkinson's disease is one of the most frequent neurodegenerative brain diseases. Its time course is slow and is characterized by progressive loss of dopaminergic and other brainstem neurons resulting in malfunctioning of the cerebral neuronal systems responsible for motor functions. The clinical signs are slowness of movement, muscle rigidity and rest-tremor amongst other features. The cause of the disease is unknown, but recently involvement of genetic factors is being researched. Positron emission tomography (PET) allows in vivo determination of striatal dopaminergic activity. This has increased our insight in the pathophysiology of the disease and permits direct study of disease progression at a biochemical level and equally to monitor whether potential neuroprotective interventions are indeed effective. Thus far no drug has emerged but promising substances are currently being studied.

Lev, N. and E. Melamed (2001). "Heredity in Parkinson's disease: new findings." Isr Med Assoc J 3(6): 435-8.
Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies.

Levecque, C., A. Destee, et al. (2001). "No genetic association of the ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism with familial Parkinson's disease." J Neural Transm 108(8-9): 979-84.
Parkinson's disease (PD) is a neurodegenerative disorder for which genetic susceptibility has been documented in sporadic and familial cases. Recently, a polymorphism located in exon 3 at codon 18 (S18Y) of the Ubiquitin Carboxy-terminal Hydrolase-L1 (UCH-L1) gene has been associated with the disease in 2 populations of German origin and also in a Japanese population. We tested the impact of this polymorphism in a French sample of familial PD patients (n = 114) and controls (n = 93). No association was observed, indicating that this polymorphism did not confer susceptibility for familial PD in our population, even among the youngest age of onset group. This observation suggests that the previous positive results obtained may reflect mechanisms restricted to the sporadic form of the disease or to a founder effect of the disease susceptibility.

Levecque, C., A. Destee, et al. (2001). "No genetic association of the Ubiquitin Carboxy-terminal Hydrolase-L1 gene S18Y polymorphism with familial Parkinson's disease." J Neural Transm 108(8-9): 979-84.
Parkinson's disease (PD) is a neurodegenerative disorder for which genetic susceptibility has been documented in sporadic and familial cases. Recently, a polymorphism located in exon 3 at codon 18 (S18Y) of the Ubiquitin Carboxy-terminal Hydrolase-L1 (UCH-L1) gene has been associated with the disease in 2 populations of German origin and also in a Japanese population. We tested the impact of this polymorphism in a French sample of familial PD patients (n = 114) and controls (n = 93). No association was observed, indicating that this polymorphism did not confer susceptibility for familial PD in our population, even among the youngest age of onset group. This observation suggests that the previous positive results obtained may reflect mechanisms restricted to the sporadic form of the disease or to a founder effect of the disease susceptibility.

Link, C. D. (2001). "Transgenic invertebrate models of age-associated neurodegenerative diseases." Mech Ageing Dev 122(14): 1639-49.
Transgenic Drosophila melanogaster and Caenorhabditis elegans strains have been engineered to express human proteins associated with neurodegenerative diseases. These model systems include transgenic animals expressing beta-amyloid peptide (Alzheimer's disease), polyglutamine repeat proteins (Huntington's disease, Spinocerebellar ataxia), and alpha-synuclein (Parkinson's disease). In most of these invertebrate models, some aspects of the human diseases are reproduced. Although expression of all these proteins in transgenic mice has been instructive, the invertebrate models offer experimental advantages (e.g. forward genetic screens) that can potentially address some of the outstanding questions regarding the cellular processes underlying these diseases. This review considers what has been learned from these invertebrate models, and speculates what further insight may be gained from them.

Lippa, C. F., M. L. Schmidt, et al. (2001). "Alpha-synuclein in familial Alzheimer disease: epitope mapping parallels dementia with Lewy bodies and Parkinson disease." Arch Neurol 58(11): 1817-20.
BACKGROUND: Alpha-synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for alpha-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms. OBJECTIVE: To investigate the alpha-synuclein epitope mapping properties of LBs in familial Alzheimer disease. DESIGN AND SETTING: We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the alpha-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy. RESULTS: The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from alpha-synuclein aggregates that occurred in multiple system atrophy. CONCLUSIONS: These data suggest that the epitope profiles of alpha-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of alpha-synuclein aggregation is the same within cell types but distinctive between cell types.

Liu, P., Z. Liu, et al. (2001). "[Genetic polymorphisms of cytochrome P450 1A1 and susceptibility of early-onset Parkinson's disease]." Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18(4): 283-5.
OBJECTIVE: To assess the possible association between the Msp I polymorphisms of cytochrome P450 1A1(CYP1A1) and the susceptibility of early-onset Parkinson's disease among Hans in the northern part of China. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to analyze three genotypes A, B and C in 3'flanking region of CYP1A1 in 126 patients with idiopathic early-onset Parkinson's disease and 172 healthy controls. RESULTS: The frequencies of genotypes A, B and C in patients were 41.3%, 43.6% and 15.1% while those in the controls were 34.9%, 51.7% and 13.4%, respectively. No statistically significant difference in the frequencies of the three genotypes was observed between the two groups. The frequencies of two alleles were of no significant difference between the patients and controls. CONCLUSION: The above results suggest that the Msp I polymorphisms of cytochrome P450 1A1 itself might not be associated with idiopathic early-onset Parkinson's disease.

Louis, E. D., G. Levy, et al. (2001). "Clinical correlates of action tremor in Parkinson disease." Arch Neurol 58(10): 1630-4.
BACKGROUND: Action tremor is often noted in patients with Parkinson disease (PD), yet the clinical correlates of this type of tremor have been the focus of few studies. It is not clear whether this action tremor is a manifestation of the underlying basal ganglia disease. OBJECTIVE: To determine whether the severity of action tremor in PD is associated with age, age at disease onset, disease duration, levodopa dose, severity of rest tremor, or other motor (ie, bradykinesia, rigidity) and nonmotor manifestations of PD. METHODS: Patients with PD (N = 197) were ascertained as part of a familial aggregation study. All patients underwent a neurological examination. Rest tremor was rated with the Unified Parkinson Disease Rating Scale; and action tremor, with the Washington Heights-Inwood Genetic Study of Essential Tremor Rating Scale. RESULTS: Action tremor was present in 184 (93.4%) of 197 patients. Four patients (2%) met criteria for definite essential tremor. The action tremor score was not associated with age, age at onset, or disease duration. The action tremor score was associated with the rest tremor score (r = 0.37; P<.001), and more strongly with the ipsilateral than contralateral rest tremor score. The association between the action tremor score and the rest tremor score was diminished but still significant (r = 0.21, P<.02) even when we excluded these 63 patients with re-emergent tremor. Neither the action nor the rest tremor score was associated with the bradykinesia or rigidity scores, Hoehn and Yahr scale score, or modified Mini-Mental State Examination score. CONCLUSIONS: Action tremor was associated with rest tremor in PD, suggesting that, at least in part, action tremor is a manifestation of the underlying basal ganglia disease. Neither tremor was associated with other motor and nonmotor manifestations of PD. This in turn suggests that tremor in PD may represent an underlying pathophysiological process different from these other manifestations.

Maimone, D., R. Dominici, et al. (2001). "Pharmacogenomics of neurodegenerative diseases." Eur J Pharmacol 413(1): 11-29.
Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.

Mak, W. and S. L. Ho (2001). "The impact of molecular biology on clinical neurology." Hong Kong Med J 7(1): 40-9.
Advances in molecular biology have increased our understanding of both inherited and sporadic forms of neurological disease. In this review, the impact of these advances is discussed in relation to specific neurological conditions. These include the hereditary neuropathies and ataxias, Huntington's disease, and the muscular dystrophies, as well as Alzheimer's disease, Parkinson's disease, and motor neuron disease. Genetic channelopathies, such as familial hemiplegic migraine, are also described. Although knowledge in this area overall is still relatively scant, current advances in molecular biology have helped in the reclassification of some neurological disorders, thereby providing a further step towards the development of rational therapies to treat these conditions.

Mark, M. H. (2001). "Lumping and splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration." Neurol Clin 19(3): 607-27, vi.
The atypical parkinsonian or Parkinson Plus syndromes are often difficult to differentiate from Parkinson's disease and each other. In this article, the clinicopathological characteristics of dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration are discussed. These disorders, although clinically distinct, may have more similarities than previously thought, based on modern immunocytochemical techniques and new genetic findings. These intriguing interconnections at a basic molecular level have provided the scientific rationale for lumping these diseases into two groups, the synucleinopathies and the tauopathies.

Martin, E. R., W. K. Scott, et al. (2001). "Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease." Jama 286(18): 2245-50.
CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Maruyama, W. (2001). "[Pathogenesis of idiopathic Parkinson's disease]." Nippon Ronen Igakkai Zasshi 38(4): 494-7.
The pathogenesis of idiopathic Parkinson's disease (PD) remains to be elucidated. The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suggests that neurotoxins in the human brain may cause selective depletion of striatal dopamine neurons, a hallmark of PD. An endogenous isoquinoline, N-methyl(R)salsolinol is a most promising neurotoxin candidate, and it was proved to be selectively toxic to dopamine neurons in the rat brain by in vivo experiments. The level of N-methyl(R)salsolinol in the cerebrospinal fluid obtained from PD patients was significantly higher than control. N-Methyl(R)salsolinol is synthesized by 2 enzymatic reactions from dopamine; condensation of dopamine with acetaldehyde into (R)salsolinol by (R)salsolinol synthase and N-methylation of (R)salsolinol by neutral(R)salsolinol N-methyltransferase. The second enzyme, which catabolizes the N-methylation of (R)salsolinol, was found to determine the level of the neurotoxin in the brain. The activity of neutral(R)salsolinol N-methyltransferase was examined using lymphocytes prepared from PD patients, normal controls and diseased controls as enzyme source. A significant increase in the activity was confirmed in lymphocytes from PD cases compared to normal- and diseased-control. Studies to clarify the environmental and genetic factors determining the activity of the enzyme are now under the way. The cytotoxicity of N-methyl(R)salsolinol was examined using a cultured cell model. N-Methyl(R)salsolinol was found to induce apoptotic cell death in a dose-dependent way. The mechanism of apoptosis was clarified to be mediated by collapse in mitochondrial membrane potential, activation of caspase 3 and fragmentation of nuclear DNA. In addition, propargylamines protected the cells from apoptosis. It was suggested that N-methyl(R)salsolinol and propargylamines have specific binding sites in mitochondria which regulate the death signal transduction. Propargylamines might be applicable as neuroprotective drugs, which can be orally administrated to PD patients.

Mattson, M. P., W. Duan, et al. (2001). "Neurodegenerative disorders and ischemic brain diseases." Apoptosis 6(1-2): 69-81.
Degeneration and death of neurons is the fundamental process responsible for the clinical manifestations of many different neurological disorders of aging, incuding Alzheimer's disease, Parkinson's disease and stroke. The death of neurons in such disorders involves apoptotic biochemical cascades involving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family members), mitochondrial alterations and caspase activation. Both genetic and environmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor protein and presenilin genes can cause Alzheimer's disease, while head injury is a risk factor for both Alzheimer's and Parkinson's diseases. At the cellular level, neuronal apoptosis in neurodegenerative disorders may be triggered by oxidative stress, metabolic compromise and disruption of calcium homeostasis. Neuroprotective (antiapoptotic) signaling pathways involving neurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of neurodegenerative disorders. A better understanding of the molecular underpinnings of neuronal death is leading directly to novel preventative and therapeutic approaches to neurodegenerative disorders.

Mazzio, E., J. Huber, et al. (2001). "Effect of antioxidants on L-glutamate and N-methyl-4-phenylpyridinium ion induced-neurotoxicity in PC12 cells." Neurotoxicology 22(2): 283-8.
The neuropathology associated with Parkinson's disease within and around the substantia nigra is thought to involve excessive production of free radicals, dopamine autoxidation, defects in the expression of glutathione peroxidase, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and N-methyl-4-phenylpyridinium ion (MPP+), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. In the present study, several dietary antioxidant compounds, monoamine oxidase inhibitors and ergogenic compounds were examined for protective action against neurotoxicity induced by L-glutamate (15 mM) or MPP+-HCl (5 mM) in a plastic adhering variant of murine pheochromocytoma cells. The results show no significant protective effects exhibited by azulene, (+)-catechin, curcrumin, (-)-epigallocatechin gallate, green tea, morin, pygnogenol, silymarin, clove oil, garlic oil or rosemary, extract. Compounds, which were effective in providing protection against L-glutamate-induced cell death, were coenzyme Q-0, coenzyme Q-10, L-deprenyl and N-acetyl-L-cysteine. Compounds, which provided protection against MPP+-HCl toxicity, were allopurinol, coenzyme Q-10, L-deprenyl, N-acetyl-L-cysteine and sesame oil. In both models, significant protection was achieved in the presence of coenzyme Q-10, L-deprenyl and N-acetyl-L-cysteine. These results indicate that the mechanism of cell death in both of these toxicity models is most likely not related to the destructive effects of free radicals.

Migliore, L., R. Scarpato, et al. (2001). "Chromosome and oxidative damage biomarkers in lymphocytes of Parkinson's disease patients." Int J Hyg Environ Health 204(1): 61-6.
As cancer development usually results from exposure to several environmental risk factors in interaction with the genetic susceptibility of the host, it could be of interest to investigate if neurodegeneration, as occurs in Parkinson's disease (PD) patients can be attributed at least partially, to environmental risk factors. There is growing evidence that oxidative stress could play a significant role as a risk factor in the aetiology and pathogenesis of neurodegenerative diseases, emphasising the need for new individual and human-based approaches. The aim of our research is to explore the relation between chromosome instability and oxidative stress biomarkers in Parkinson's disease using a variety of strategies. We determined peripheral markers for oxidative damage in PD by testing for spontaneous and induced chromosomal damage, DNA strand breaks, oxidised pyrimidines and altered purines both in peripheral blood and cultured lymphocytes. We also measured glutathione S-transferase activity in the plasma of patients and controls. Compared to healthy controls, PD patients show higher frequencies of micronuclei (17.2 +/- 4.8 vs. 9.0 +/- 3.4, p < 0.001) and a significant increase in the levels of single strand breaks (SSB). Significant differences were also obtained in the distribution of oxidised purine bases between the two groups. Preliminary data obtained by fluorescence in situ hybridization analysis showed that the percentage of centromere negative micronuclei is higher than that of centromere positive micronuclei. Glutathione S-transferase activity in plasma from PD patients and controls was also measured and the enzymatic activity in PD patients was lower than in healthy controls.

Miyamoto, K., A. Ikemoto, et al. (2001). "A case of frontotemporal dementia and parkinsonism of early onset with progressive supranuclear palsy-like features." Clin Neuropathol 20(1): 8-12.
We report a patient with frontotemporal degeneration and parkinsonism with mental retardation. The patient was a 54-year-old man who had parkinsonism that resembled progressive supranuclear palsy, frontotemporal degeneration and myoclonus. His family included many affected members. Neuropathologically, there was degeneration of the frontal and temporal cortices, the basal ganglia, the brainstem and the cerebellum. Microscopically, neuronal loss was severe in the frontal and temporal cortex, the globus pallidus, substantia nigra, red nucleus and dentate nucleus. Fibrillary changes were found in neurons and glia that were immunostained for tau. Although we could not define the genetic abnormalities, we thought that this case might have involved frontotemporal dementia and parkinsonism linked to chromosome 17.

Mochizuki, H., H. Hayakawa, et al. (2001). "An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease." Proc Natl Acad Sci U S A 98(19): 10918-23.
Adeno-associated virus (AAV) vector delivery of an Apaf-1-dominant negative inhibitor was tested for its antiapoptotic effect on degenerating nigrostriatal neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. The wild-type caspase recruitment domain of Apaf-1 was used as a dominant negative inhibitor of Apaf-1 (rAAV-Apaf-1-DN-EGFP). An AAV virus vector was used to deliver it into the striatum of C57 black mice, and the animals were treated with MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was not changed on the rAAV-Apaf-1-DN-EGFP injected side compared with the noninjected side. We also examined the effect of a caspase 1 C285G mutant as a dominant negative inhibitor of caspase 1 (rAAV-caspase-1-DN-EGFP) in the same model. However, there was no difference in the number of tyrosine hydroxylase-positive neurons between the rAAV-caspase-1-DN-EGFP injected side and the noninjected side. These results indicate that delivery of Apaf-1-DN by using an AAV vector system can prevent nigrostriatal degeneration in MPTP mice, suggesting that it could be a promising therapeutic strategy for patients with Parkinson's disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.

Moilanen, J. S., J. M. Autere, et al. (2001). "Complex segregation analysis of Parkinson's disease in the Finnish population." Hum Genet 108(3): 184-9.
The risk of Parkinson's disease (PD) is higher among relatives of affected individuals than among other members of the population, and most family studies have suggested autosomal dominant inheritance, although both autosomal dominant and recessive susceptibility genes have recently been identified. We carried out a complex segregation analysis with POINTER to assess the mode of inheritance of PD in the population of northern Finland. Nuclear families (n=265) were identified through a proband with idiopathic PD. The analysis was first carried out for the total data set, and then the heterogeneity between early-onset (proband under 55 years at onset) and late-onset families was examined. Finally, families with more than one affected individual were analyzed separately. The sporadic model was rejected (P<0.0001). Significant heterogeneity was found between the early-onset and late-onset families, suggesting that major genes have a greater role in early-onset PD than in late-onset PD and that the etiology of idiopathic PD is heterogeneous, even in the Finnish population, which has evolved from a small group of founders. The analysis of familial PD supported the hypothesis that a major locus was present in this subset, but it was not possible to distinguish between a recessive model with a high penetrance and a dominant model with lower penetrance.

Morris, S. and D. Powell (2001). "Rats and risk." Lancet 357(9252): 309-10.

Munoz, E., P. Pastor, et al. (2001). "[Sporadic and familial Parkinson's disease: comparative study]." Med Clin (Barc) 116(16): 601-4.
BACKGROUND: Several studies have shown that 13 to 33% of patients with Parkinson's disease (PD) exhibit a positive familial history. The goals of this work were to identify patients with familial PD and to analyse whether there existed distinctive features between familial and sporadic cases. PATIENTS AND METHOD: 402 patients with PD from the Hospital Clinic i Universitari of Barcelona were evaluated prospectively. Clinical assessment was done using different scales in 169 patients. The disease was classified as tremorigenic, rigid or mixed according to the predominant symptoms. RESULTS: The frequency of familial PD was 13%. The age at onset was not different between familial and sporadic cases but it was significantly higher in females (57.4 [13] years) than in males (54.8 [11.4] years) (p < 0.05). The tremorigenic type of PD was more common in familial cases (35.5%) (p Z 0.05). In familial PD cases, the age at onset was lower in descendents (53 [13] years) than in parents (68 [7.8] years) (p = 0.001). CONCLUSIONS: Genetic factors may play an important role in the development of PD and gender-associated factors may modulate the age at onset. Familial PD cases differ from sporadic cases in the higher frequency of predominantly tremorigenic forms. The lower age at onset in descendents than in parents suggests the existence of a genetic anticipation phenomenon in familial PD.

Muthane, U., S. Jain, et al. (2001). "Hunting genes in Parkinson's disease from the roots." Med Hypotheses 57(1): 51-5.
Parkinson's disease (PD), a common, neurodegenerative disorder, has a worldwide distribution. The genetic basis of PD is not well understood, although some recent leads have emerged. Epidemiological studies suggest that there is significant variation in the prevalence of PD between different populations and rates are highest in populations of European origin. Significant differences in molecular pathology in PD and control brain tissue have been observed between African, British and Indian populations. In view of this epidemiological and pathological evidence, it is proposed that allelic variations in genes that predispose to PD may account for the ethnic variation. Advances in our knowledge about the human genome will allow us to make detailed comparisons between affected and control subjects in different populations. This may help us to understand the reasons for the variation, and a better understanding of the genetic processes underlying the disease process. Copyright 2001 Harcourt Publishers Ltd.

Nagar, S., R. C. Juyal, et al. (2001). "Mutations in the alpha-synuclein gene in Parkinson's disease among Indians." Acta Neurol Scand 103(2): 120-2.
OBJECTIVE: To investigate the prevalence of G88C, G209A and any other mutation(s) in exons 3 and 4 of the alpha-synuclein gene in Indian patients with Parkinson's disease (PD). METHODS: A total of 169 PD patients comprising 18 familial, 3 juvenile, 48 early onset and 100 sporadic cases were included in this study. Genomic DNA was amplified by PCR using primers specific for Exons 3 and 4. Mutations at G88C and G209A were screened following restriction enzyme digestion of the PCR product. Direct PCR product sequencing of entire exons 3 and 4 was carried out for at least one proband each from the 10 familial cases. RESULTS: Neither G88C and G209A mutations nor any other mutation in exons 3 and 4 was found in the PD patients analysed. CONCLUSION: The G88C and G209A mutations do not seem to be the predominant genetic determinant of PD among Indians.

Nakamura, K., V. P. Bindokas, et al. (2001). "Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons." J Biol Chem 276(37): 34402-7.
Increased oxidative stresses are implicated in the pathogenesis of Parkinson's disease, and dopaminergic neurons may be intrinsically susceptible to oxidative damage. However, the selective presence of tetrahydrobiopterin (BH(4)) makes dopaminergic neurons more resistant to oxidative stress caused by glutathione depletion. To further investigate the mechanisms of BH(4) protection, we examined the effects of BH(4) on superoxide levels in individual living mesencephalic neurons. Dopaminergic neurons have intrinsically lower levels of superoxide than nondopaminergic neurons. In addition, inhibiting BH(4) synthesis increased superoxide in dopaminergic neurons, while BH(4) supplementation decreased superoxide in nondopaminergic cells. BH(4) is also a cofactor in catecholamine and NO production. In order to exclude the possibility that the antioxidant effects of BH(4) are mediated by dopamine and NO, we used fibroblasts in which neither catecholamine nor NO production occurs. In fibroblasts, BH(4) decreased baseline reactive oxygen species, and attenuated reactive oxygen species increase by rotenone and antimycin A. Physiologic concentrations of BH(4) directly scavenged superoxide generated by potassium superoxide in vitro. We hypothesize that BH(4) protects dopaminergic neurons from ordinary oxidative stresses generated by dopamine and its metabolites and that environmental insults or genetic defects may disrupt this intrinsic capacity of dopaminergic neurons and contribute to their degeneration in Parkinson's disease.

Nass, R., D. M. Miller, et al. (2001). "C. elegans: a novel pharmacogenetic model to study Parkinson's disease." 7(3): 185-191.
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Although the use of vertebrate and tissue culture systems continue to provide valuable insight into the pathology of the neurodegeneration, the molecular determinants involved in the etiology of the disease remain elusive. Because of the high conservation of genes and metabolic pathways between invertebrates and humans, as well as the availability of genetic strategies to identify novel proteins, protein interactions and drug targets, genetic analysis using invertebrate model systems has enormous potential in deducing the factors involved in neuronal disease. In this article, we discuss the opportunities for the use of the nematode Caenorhabditis elegans (C. elegans) for gaining insight into the molecular mechanisms and pathways involved in PD.

Pal, P. K., Z. K. Wszolek, et al. (2001). "Positron emission tomography of dopamine pathways in familial Parkinsonian syndromes." 8(1): 51-56.
Positron emission tomography (PET) scan is considered to be the most useful tool with which to assess the integrity of nigrostriatal function in the living brain. Recently, different genetic defects have been associated with a variety of familial parkinsonian syndromes, the clinical phenotypes of which have varying degrees of similarities to idiopathic parkinsonism (IP), (sporadic Parkinson's disease). This review summarizes: (1) the PET scan findings (fluorodopa uptake and raclopride binding) in both familial parkinsonian syndromes and IP; and (2) the similarities and differences of the clinical and PET features between familial parkinsonian syndromes and IP. This analysis demonstrates that more similarities than differences exist in PET scan findings in the different familial parkinsonian syndromes with the exception of pallido-ponto-nigral degeneration (PPND), that is perhaps best considered as multisystem degeneration. As a result of this analysis, we believe that while different genetic defects may underlie different mechanisms of nigrostriatal degeneration, the final pattern of nigrostriatal dysfunction is essentially similar to that of IP. 'Parkinson's disease', therefore, may not represent a single disease entity, but rather the final manifestation of different pathogenetic mechanisms-mediated by genetic or environmental factors, or an interaction of genetic and environmental factors.

Papapetropoulos, S., C. Paschalis, et al. (2001). "Clinical phenotype in patients with alpha-synuclein Parkinson's disease living in Greece in comparison with patients with sporadic Parkinson's disease." J Neurol Neurosurg Psychiatry 70(5): 662-5.
OBJECTIVE: An Ala53Thr mutation of the alpha-synuclein gene has been recently identified as a rare cause of autosomal Parkinson's disease (PD). The clinical characteristics of 15 patients with PD living in Greece with the Ala53Thr alpha-synuclein mutation (alpha-synPD) were compared with patients with sporadic Parkinson's disease (sPD). METHODS: An investigator, blind to the results of the genetic analysis, examined 15 patients with alpha-synPD and 52 consecutive patients with sPD. Demographic data, age at onset of the illness, modality of presentation, and duration of PD were collected. The unified Parkinson's disease rating scale, the Hoehn and Yahr scale, and the Schwab-England scale were completed. The patients with alpha-synPD were matched for duration of disease with 32 of the 52 patients with sporadic PD (MsPD group). RESULTS: Patients with the alpha-synuclein mutation were significantly younger (mean 7.6 years), showed the first sign of the disease significantly earlier in life (mean 10.8 years), and had significantly longer duration of the disease compared with patients with sPD. Tremor at onset of the disease was present in only one (6.7%) of the patients with alpha-synPD, whereas it was present in 32 (61.5%) of the patients with sPD (p=0.0006). During the course of the disease one patient in the alpha-synPD group went on to develop tremor compared with six patients in the sPD group. Rigidity, bradykinesia, postural instability, orthostatic hypotension, intellectual impairment, depression, complications of therapy, and clinical severity of the disease at the time of examination did not differ significantly between patients with alpha-synPD and those with sPD, or between patients with alpha-synPD and the MsPD group. CONCLUSION: The younger age at onset of the illness, the much lower prevalence of tremor, and the longer duration of the disease characterise the clinical phenotype in this sample of patients with alpha-synPD. The other symptoms and signs of the illness did not seem to differentiate the patients with alpha-synPD from those with sPD.

Park, K. W., M. A. Eglitis, et al. (2001). "Protection of nigral neurons by GDNF-engineered marrow cell transplantation." Neurosci Res 40(4): 315-23.
Marrow stromal cells, which have many characteristics of stem cells, populate various non-hematopoietic tissues including the brain. In the present study, the cDNA for the dopaminergic neurotrophic factor Glial Cell Line-Derived Neurotrophic Factor (GDNF) was delivered using marrow cells in the mouse 1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) model of Parkinson's disease. Following cross-sex intravenous bone marrow transplantation with male donor cells that had been transduced with GDNF (GDNF-BMT) or with non-manipulated marrow (Control-BMT), female recipient mice were subjected to systemic MPTP injections. Eight weeks after neurotoxin exposure, more tyrosine hydroxylase immunoreactive nigral neurons and striatal terminal density were observed in the GDNF-BMT mice compared with the Control-BMT group. In addition, following the expected initial behavioral hyperactivity in both groups, a significant difference in motor activity was detected between the two groups. GDNF immunoreactive male donor marrow derived cells were detected in the brains of GDNF-BMT mice but not in controls. These data indicate that marrow derived cells that seed the brain can express biologically active gene products and, therefore, can function as effective vehicles for therapeutic gene transfer to the brain.

Payami, H., N. Lee, et al. (2001). "Parkinson's disease, CYP2D6 polymorphism, and age." Neurology 56(10): 1363-70.
OBJECTIVE: PD may be caused by genetic susceptibility to neurotoxins. CYP2D6 is a candidate gene for PD because it regulates drug and toxin metabolism, but association studies have been inconsistent. The aim of this study was to test if the CYP2D6*4 allele (poor metabolizer phenotype) is associated with earlier age at onset. METHODS: Five hundred seventy-six patients with PD and 247 subjects without PD were studied using standard diagnostic, genotyping, and statistical techniques. RESULTS: Surprisingly, mean onset age was significantly later in *4-positive patients. Frequency of *4 was significantly higher in late-onset PD than early-onset PD. When early- and late-onset PD were analyzed separately, *4 had no effect on onset age; hence, the association with delayed onset was likely an artifact of an elevated *4 frequency in late-onset PD. Contrary to a common assumption that CYP2D6 frequencies do not change with age, *4 frequency rose significantly with advancing age, both in patients with PD (from 0.16 at mean age of 56.5 years to 0.21 at mean age of 72) and subjects without PD (from 0.09 at mean age of 45.5 years to 0.21 at mean age of 72). *4 Frequencies in patients with early- and late-onset PD, although different from each other, were in agreement with similarly aged subjects without PD, suggesting the elevated *4 frequency in late-onset PD was likely an age effect, unrelated to PD. CONCLUSION: The CYP2D6*4 allele is not associated with earlier PD onset. *4 May be associated with survival. Inconsistent results from allelic association studies may have been due to an unrecognized age effect.

Periquet, M., C. Lucking, et al. (2001). "Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects." Am J Hum Genet 68(3): 617-26.
A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Racette, B. A., L. McGee-Minnich, et al. (2001). "Welding-related parkinsonism: clinical features, treatment, and pathophysiology." Neurology 56(1): 8-13.
OBJECTIVE: To determine whether welding-related parkinsonism differs from idiopathic PD. BACKGROUND: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. METHODS: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations. RESULTS: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. CONCLUSIONS: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

Rathke-Hartlieb, S., P. J. Kahle, et al. (2001). "Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice." J Neurochem 77(4): 1181-4.
Environmental and genetic factors that contribute to the pathogenesis of Parkinson's disease are discussed. Mutations in the alpha-synuclein (alphaSYN ) gene are associated with rare cases of autosomal-dominant Parkinson's disease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]alphaSYN under the control of a neurone-specific Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed somal and neuritic accumulation of transgenic [A30P]alphaSYN in TH-positive neurones in the substantia nigra. However, there was no difference in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum between these transgenic mice and non-transgenic littermates. To investigate whether forced expression of [A30P]alphaSYN increased the sensitivity to putative environmental factors we subjected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. The MPTP-induced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]alphaSYN transgenic mouse lines compared with wild-type controls. These results suggest that mutations and forced expression of alphaSYN are not likely to increase the susceptibility to environmental toxins in vivo.

Reid, A. H., S. McCall, et al. (2001). "Experimenting on the past: the enigma of von Economo's encephalitis lethargica." J Neuropathol Exp Neurol 60(7): 663-70.
Encephalitis lethargica (EL) was a complex and mysterious disease that appeared around the same time as the great influenza pandemic of 1918. The contemporaneous relationship of the 2 diseases led to speculation that they were causally related. Contemporary and subsequent observers conjectured that the influenza virus, directly responsible for the deaths of more than 20 million people, might also have been the cause of EL. A review of the extensive literature by observers of the EL epidemic suggests that most contemporary clinicians, epidemiologists, and pathologists rejected the theory that the 1918 influenza virus was directly responsible for EL. Disappearance of the acute form of EL during the 1920s has precluded direct study of this entity. However, modern molecular biology techniques have made it possible to examine archival tissue samples from victims of the 1918 pandemic in order to detect and study the genetic structure of the killer virus. Similarly, tissue samples from EL victims can now be examined for evidence of infection by the 1918 influenza virus.

Reilly, C. E. (2001). "Glial cell line-derived neurotrophic factor (GDNF) prevents neurodegeneration in models of Parkinson's disease." J Neurol 248(1): 76-8.

Ruse, C. E. and S. G. Parker (2001). "Molecular genetics and age-related disease." Age Ageing 30(6): 449-454.
Maintenance and repair processes are crucial to the pathogenesis of ageing and late-onset disease. Thus, there is increasing recognition of the importance of genetic factors in the development of late-onset conditions such as stroke, Parkinson's disease and osteoporosis, and accumulating evidence for a genetic component in the development of chronic obstructive pulmonary disease. We review the approaches and problems in the genetic investigation of complex disorders in old age, taking chronic obstructive pulmonary disease as an example.

Schwarz, E. J., R. L. Reger, et al. (2001). "Rat marrow stromal cells rapidly transduced with a self-inactivating retrovirus synthesize L-DOPA in vitro." Gene Ther 8(16): 1214-23.
Autologous bone marrow stromal cells engineered to produce 3,4,-dihydroxyphenylalanine (L-DOPA) can potentially be used as donor cells for neural transplantation in Parkinson's disease. Here, we examined the possibility of using several different promoters and either a self-inactivating retrovirus (pSIR) or standard retroviruses to introduce into marrow stromal cells (MSCs), the two genes necessary for the cells to synthesize L-DOPA. pSIR vectors were constructed using the mouse phosphoglycerate kinase-1 (PGK) promoter or the cytomegalovirus (CMV) promoter to drive expression of either a GFP reporter gene or a bicistronic sequence containing the genes for human tyrosine hydroxylase type I (TH) and rat GTP cyclohydrolase I (GC) separated by an internal ribosome entry site (IRES). rMSCs were successfully transduced with both standard retroviral vectors and pSIR containing the PGK promoter. Transduced rMSCs expressed GFP (90.4--94.4% of cells) or were able to synthesize and secrete L-DOPA (89.0--283 pmols/10(6) cells/h). After transduced rMSCs were plated at low density (3--6 cells/cm(2)), the cells expanded over 1000-fold in 3--4 weeks, and the rMSCs continued to either express GFP or produce L-DOPA. Furthermore, two high-expressing clones were isolated and expanded at low-density from rMSCs transduced with pSIR driven by the PGK promoter (97.0% GFP+ or 1096.0 pmols L-DOPA/10(6) cells/h).

Scott, W. K., M. A. Nance, et al. (2001). "Complete genomic screen in Parkinson disease: evidence for multiple genes." Jama 286(18): 2239-44.
CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Shao, M., Z. Liu, et al. (2001). "[Polymorphism of MAO-B gene and NAD(P)H: quinone oxidoreductase gene in Parkinson's disease]." Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18(2): 122-4.
OBJECTIVE: To investigate whether Parkinson's disease(PD) is associated with genetic polymorphism of intron 13 of monoamine oxidase B(MAO-B) and NAD(P)H: quinone oxidoreductase(NQO1) gene cDNA 609C to T. METHODS: Association study was performed in 126 PD patients and 136 healthy control subjects matched for age, sex and origin. The NQO1 gene polymorphism was analyzed with the polymerase chain reaction-restriction fragment length polymorphism, the polymorphism of intron 13 of MAO-B was analyzed by allele- specific PCR. RESULTS: The allelic frequency of the mutant T allele of NQO1 gene was significantly higher in the PD patients as compared to the controls(P<0.05). The relative risk of suffering from PD increased (OR=3.8) in the individuals with T allelic genotype of NQO1 gene, and the odds ratio was as high as 5.7 when the individuals with A or AA genotype of MAO-B gene coexisted with the T allele genotype of NQO1 gene. CONCLUSION: The cDNA 609T allele of NQO1 gene might be a risk factor of PD, which could be associated with the genetic susceptibility of PD. The high activity A or AA genotype of MAO-B and the low activity genotype of NQO1 gene might have synergistic effect. When both genotypes coexist, the risk of suffering PD will be increased greatly.

Shastry, B. S. (2001). "Parkinson disease: etiology, pathogenesis and future of gene therapy." Neurosci Res 41(1): 5-12.
Parkinson disease (PD) is a progressive neurological disorder with a prevalence of 1-2% in people over the age of 50. It has a world-wide distribution and has no gender preference. The neurological hallmark of PD is the presence of Lewy bodies and is characterized by the degeneration of nigrostriatal dopaminergic neurons. The causes of PD are unknown but considerable evidence suggests a multifactorial etiology involving genetic and environmental factors. A molecular genetic approach identified three genes and at least two additional loci in rare familial forms of PD. Two of these genes are involved in the ubiquitin mediated pathway of protein degradation and the third one is a highly expressed protein in the synaptic terminal and is called alpha-synuclein. In animal models, it has been shown that use of the household pesticide which is known to contain rotenone, causes PD. Thus, a combined action of genetic and environmental factors is responsible for the pathogenesis of PD. Although use of levodopa or dopamine agonists can substantially reduce clinical symptoms, and transplantation of fetal nerve tissue still remains as an alternative therapy (although it has been recently shown to be having no overall benefit), directed delivery of glial cell derived neurotrophic factor (known to have trophic effects on dopaminergic neurons) may also be a beneficial therapeutic option for PD patients.

Sherer, T. B., R. Betarbet, et al. (2001). "Pathogenesis of Parkinson's disease." Curr Opin Investig Drugs 2(5): 657-62.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway and the appearance of cytoplasmic proteinaceous aggregates known as Lewy bodies. Studies of familial PD have uncovered rare causative mutations in genes, including alpha-synuclein. Mutations or oxidative modification of alpha-synuclein causes it to aggregate; alpha-synuclein is a major component of the Lewy body in both familial and sporadic PD. Biochemical analysis has implicated mitochondrial dysfunction in PD. Epidemiological studies indicate a role of exposure to pesticides, some of which are mitochondrial toxins. Mitochondrial dysfunction, resulting from genetic defects, environmental toxins, or a combination of the two, may cause alpha-synuclein aggregation and produce selective neurodegeneration through mechanisms involving oxidative stress and excitotoxicity. Efforts to better define PD pathogenesis should reveal novel therapeutic targets.

Shimo, Y., M. Takanashi, et al. (2001). "[A-56-year-old woman with parkinsonism, whose mother had Parkinson's disease]." No To Shinkei 53(5): 495-505.
We report a 56-year-old woman with progressive gait disturbance. Her mother had Parkinson's disease with onset at age 70. She died at age 74 and the post-mortem examination confirmed the diagnosis of Lewy body positive Parkinson's disease. The patient was well until the age of 50(1995) when she noted an onset of resting tremor and difficulty of gait. She also developed delusional ideation and was admitted to a psychiatric service of another hospital, where a major tranquilizer was given. The delusion disappeared but she developed marked rigidity. The major tranquilizer was discontinued and an anticholinergic and amantadine HCl were given. She showed marked improvement to Hoehn and Yahr stage II and was discharged. In 1995, when she was 52 years of the age, she developed delusion again and a major tranquilizer was given. She developed marked parkinsonism again and became Hoehn and Yahr stage V. The major tranquilizer was discontinued and she was treated with levodopa/carbidopa, trihexyphenidyl, bromocriptine, and dops. She improved remarkably to stage II. She was admitted to our service on October 8, 1996 for drug adjustment. She was alert and not demented. She was anxious but delusion or hallucination was noted. Higher cerebral functions were intact. Cranial nerve functions were also intact except for masked face and small voice. Her posture was stooped and steps were small. She showed retropulsion and moderate bradykinesia. Resting tremor was noted in her left hand. Rigidity was noted in both legs. No cerebellar ataxia or weakness was noted. Deep tendon reflexes were within normal range and sensation was intact. Her cranial MRI revealed some atrophic changes in the putamen, in which a T 2-high signal linear lesion was seen along the lateral border of the putamen bilaterally. In addition, posterior part of the putamen showed T 2-low signal intensity change. She was treated with 1.6 mg of talipexole, 6 mg of trihexyphenidyl, and 100 mg of L-dops. She was in stage III of Hoehn and Yahr. She developed neurogenic bladder with a large amount of residual urine for which she required catheterization. She was transferred to another hospital. Despite drug adjustment, she lost response to levodopa and her parkinsonism deteriorated gradually. She also developed syncope orthostatic hypotension. In April of 1998, she developed intracerebral hemorrhage and was admitted again on April 19, 1998. She was unable to stand and showed marked akinesia and rigidity. She was in stage V of Hoehn and Yahr. Her cranial CT scan revealed bilateral high-density lesions in the posterior parietal lobes. She developed dysphagia for which she required gastrostomy. She was transferred to another hospital but her clinical condition deteriorated further. On December 22, 1999, she developed fever and dyspnea and was admitted to our service again. She developed cardial arrest at the emergency room from hypoxia. She was resuscitated; however, she was comatose with loss of brain stem reflexes. Later on she developed generalized myoclonus. She developed cardiac arrest and pronounced dead on December 28, 1999. The patient was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had striatonigral degeneration because of poor response to levodopa in the later course, autonomic failures, and MRI changes. Some other participants thought that the patient had a form of familial Parkinson's disease. Opinions were divided into these two possibilities. Post-mortem examination revealed that the substantia nigra showed intense neuronal loss and gliosis, however, no Lewy bodies were seen. In addition, intracytoplasmic inclusions were seen in oligodendrocytes. The putamen was markedly atrophic in its posterior part with marked gliosis and neuronal loss. The ventromedial part of the pontine nucleus also showed neuronal loss and intracytoplasmic glial inclusions. Pathologic diagnosis was multiple system atrophy. In the parietal lobe, an arteriovenous malformation with bleeding was noted. This is very unique case. Although her mother had Lewy body-positive Parkinson's disease, the patient had Lewy body-negative multiple system atrophy with a-synuclein-positive glial inclusions. Whether this is just a coincidental occurrence or the presence of a genetic load for Parkinson's disease might triggered her multiple system atrophy is an interesting question to be answered in future.

Sibal, L. R. and K. J. Samson (2001). "Nonhuman primates: a critical role in current disease research." Ilar J 42(2): 74-84.
This review article emphasizes the critical role of nonhuman primates (NHPs) in biomedical research. It focuses on the most recent contributions that NHPs have made to the understanding, treatment, and prevention of important infectious diseases (e.g., acquired immunodeficiency syndrome, hepatitis, malaria) and chronic degenerative disorders of the central nervous system (e.g., Parkinson's and Alzheimer's diseases). The close phylogenetic relation of NHPs to humans not only opens avenues for testing the safety and efficacy of new drugs and vaccines but also offers promise for evaluating the potential of new gene-based treatments for human infectious and genetic diseases.

Siderowf, A. (2001). "Parkinson's disease: clinical features, epidemiology and genetics." Neurol Clin 19(3): 565-78, vi.
Genetic and epidemiological studies are critical to understanding the etiology of Parkinson's Disease (PD), and may lead to rational treatments for the disease. This article reviews the clinical features, epidemiology and genetics of PD, with emphasis on insights from recent genetic and epidemiological studies.

Silverdale, M. A., S. McGuire, et al. (2001). "Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson's disease." Exp Neurol 169(2): 400-6.
High levels of both endocannabinoids and endocannabinoid receptors are present in the basal ganglia. Attention has recently focused on the role of endocannabinoids in the control of movement and in movement disorders of basal ganglia origin such as Parkinson's disease. We investigated CB1 cannabinoid receptor mRNA expression in the reserpine-treated rat model of Parkinson's disease using in situ hybridization. Reserpine treatment caused a topographically organized reduction in CB1 receptor mRNA expression in the striatum (ranging from 11.6% medially to 53.6% laterally and dorsally). No change in CB1 receptor mRNA expression was observed in the cerebral cortex or septum. This reduction in CB1 receptor mRNA expression may be secondary to increased endocannabinoid stimulation of the receptor as increased basal ganglia endocannabinoid levels have been shown to occur in this model of Parkinson's disease. The data support the idea that cannabinoid receptor antagonists may provide a useful treatment for the symptoms of Parkinson's disease. Copyright 2001 Academic Press.

Smeyne, M., O. Goloubeva, et al. (2001). "Strain-dependent susceptibility to MPTP and MPP(+)-induced parkinsonism is determined by glia." Glia 34(2): 73-80.
Parkinson's disease (PD) is a debilitating neurological disorder that strikes approximately 2% of people over age 50. Current hypotheses propose that the cause of PD is multifactorial, involving environmental agents and genetic predisposition. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism in many species, including humans and shows strain specificity in mice. The mechanism of strain specificity, however, remains unknown. Using novel chimeric murine substantia nigra cultures, we demonstrate that sensitivity to MPTP is conferred by glia and that it does not involve the MAO-B conversion of MPTP to MPP(+). C57Bl/6J dopaminergic neurons exposed to MPP(+) demonstrated a 39% loss when cultured on C57Bl/6J glia compared with 17% neuron loss when cultured on resistant SWR/J glia. Similarly, SWR/J neurons exposed to MPP(+) demonstrated a 4% loss when cultured on SWR/J glia, but a 14% loss when cultured on sensitive C57Bl/6J glia. The identification of glia as the critical cell type in the genesis of experimental Parkinsonism provides a target for the development of new anti-parkinsonian therapies.

Snaddon, J., E. K. Parkinson, et al. (2001). "Detection of functional PTEN lipid phosphatase protein and enzyme activity in squamous cell carcinomas of the head and neck, despite loss of heterozygosity at this locus." Br J Cancer 84(12): 1630-4.
The human tumour suppressor gene PTEN located at 10q23 is mutated in a variety of tumour types particularly metastatic cases and in the germline of some individuals with Cowdens cancer predisposition syndrome. We have assessed the status of PTEN and associated pathways in cell lines derived from 19 squamous cell carcinomas of the head and neck. Loss of heterozygosity is evident at, or close to the PTEN gene in 5 cases, however there were no mutations in the remaining alleles. Furthermore by Western analysis PTEN protein levels are normal in all of these SCC-HN tumours and cell lines. To assess the possibility that PTEN may be inactivated by another mechanism, we characterized lipid phosphatase levels and from a specific PIP3 biochemical assay it is clear that PTEN is functionally active in all 19 human SCCs. Our data strongly suggest the possibility that a tumour suppressor gene associated with development of SCC-HN, other than PTEN, is located in this chromosomal region. This gene does not appear to be MXI-1, which has been implicated in some other human tumour types. PTEN is an important negative regulator of PI3Kinase, of which subunit alpha is frequently amplified in SCC-HN. To examine the possibility that PI3K is upregulated by amplification in this tumour set we assessed the phosphorylation status of Akt, a downstream target of PI3K. In all cases there is no detectable increase in Akt phosphorylation. Therefore there is no detectable defect in the PI3K pathway in SCC-HN suggesting that the reason for 3q26.3 over-representation may be due to genes other than PI3K110alpha. Copyright 2001 Cancer Research Campaign.

Sopher, B. L., K. L. Koszdin, et al. (2001). "Genomic organization, chromosome location, and expression analysis of mouse beta-synuclein, a candidate for involvement in neurodegeneration." Cytogenet Cell Genet 93(1-2): 117-23.
The synuclein family of proteins is a group of primarily brain-expressed polypeptides that show a high degree of amino acid conservation. alpha-Synuclein is the best known of the synuclein family, as it is a major component of the Lewy body, a cytoplasmic inclusion characteristic of Parkinson's disease as well as a variety of related neurodegenerative disorders. With the discovery that mutations in alpha-synuclein can cause Parkinson's disease, a potential role for the other synuclein family members in neurodegenerative disease is being considered. beta-Synuclein in particular may deserve special attention, as it is co-expressed with alpha-synuclein at presynaptic nerve terminals, is subject to phosphorylation by Ca(2+) calmodulin protein kinase II, appears important for neural plasticity, and forms aggregates in the brains of patients with Parkinson's disease and a related disorder. To facilitate study of beta-synuclein, we have cloned the mouse beta-synuclein gene (Sncb) and determined its genomic organization, size, and intron-exon structure. Using an interspecific backcross mapping panel from The Jackson Laboratory, we were then able to localize Sncb to chromosome 13 at the MGD 35.0 cM position. Like the human beta-synuclein gene, Sncb appears to consist of six exons separated by five introns. Unlike the human beta-synuclein gene, the mouse ortholog possesses a variant GC 5' splice donor sequence at the exon 4 - intron 4 boundary in a highly conserved splice junction consensus. Northern blot analysis and Western blot analysis both indicate that Sncb is highly expressed in the brain. Knowledge of the genomic organization and expression pattern of Sncb will allow functional studies of its potential role in neurodegeneration to commence in the mouse. Copyright 2001 S. Karger AG, Basel

Stefanis, L., K. E. Larsen, et al. (2001). "Expression of A53T Mutant But Not Wild-Type alpha -Synuclein in PC12 Cells Induces Alterations of the Ubiquitin-Dependent Degradation System, Loss of Dopamine Release, and Autophagic Cell Death." J Neurosci 21(24): 9549-9560.
alpha-Synuclein mutations have been identified in certain families with Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies. Other genetic data indicate that the ubiquitin-dependent proteolytic system is involved in PD pathogenesis. We have generated stable PC12 cell lines expressing wild-type or A53T mutant human alpha-synuclein. Lines expressing mutant but not wild-type alpha-synuclein show: (1) disruption of the ubiquitin-dependent proteolytic system, manifested by small cytoplasmic ubiquitinated aggregates and by an increase in polyubiquitinated proteins; (2) enhanced baseline nonapoptotic death; (3) marked accumulation of autophagic-vesicular structures; (4) impairment of lysosomal hydrolysis and proteasomal function; and (5) loss of catecholamine-secreting dense core granules and an absence of depolarization-induced dopamine release. Such findings raise the possibility that the primary abnormality in these cells may involve one or more deficits in the lysosomal and/or proteasomal degradation pathways, which in turn lead to loss of dopaminergic capacity and, ultimately, to death. These cells may serve as a model to study the effects of aberrant alpha-synuclein on dopaminergic cell function and survival.

Steventon, G. B., S. Sturman, et al. (2001). "A review of xenobiotic metabolism enzymes in Parkinson's disease and motor neuron disease." Drug Metabol Drug Interact 18(2): 79-98.
The role of xenobiotic metabolising enzymes (XMEs) in disease aetiology has been under investigation by numerous researchers around the world for the last two decades. The association of a number of defects in both phase I and phase II reactions with Parkinson's disease (PD) and motor neuron disease (MND) have been extensively studied. This review of the work of the group based initially at the University of Birmingham into the functional genomics of XMEs and neurodegenerative diseases has indicated that: 1. Sub-groups of patients with PD and MND can be identified with problems in xenobiotic metabolism by in vivo or in vitro methods. 2. 38-39% of the patients with MND/PD have a defect in the S-oxidation of the mucoactive drug, carbocysteine, by an unknown cytosolic oxidase(s). The odds risk ratio for the association of this defect with these diseases was calculated to be 10.21 for MND and 10.50 for PD. 3. Patients with PD appear to have an altered substrate specificity for monoamine oxidase B substrates in an in vitro platelet assay. 4. Patients with MND have an increased capacity to S-methylate aliphatic sulphydryl compounds in an in vivo challenge as well as an in vitro erythrocyte thiol methyltransferase assay. The results of over a decade of investigations into both PD and MND indicate that these are diseases with mutifactorial origins that encompass both genetic predisposition and environmental insult.

Sunde, A. and I. Eftedal (2001). "[Embryonic stem cells and therapeutic cloning]." Tidsskr Nor Laegeforen 121(20): 2407-12.
Increased interest in the therapeutic use of human stem cells has emerged following significant progress in ongoing research. The cloning of a sheep, the isolation of human embryonic stem cells, and the discovery that adult stem cells may be reprogrammed taken together give substance to hopes that novel principles of treatment may be developed for a variety of serious conditions. Embryonic stem cells are derived from pre-embryos at the blastocyst stage and may give rise to all bodily tissues and cells. Animal models have demonstrated that embryonic stem cells when transplanted into adult hosts may differentiate and develop into cells and tissues applicable for treatment of a variety of conditions, including Parkinson's disease, multiple sclerosis, spinal injuries, cardiac stroke and cancer. Transplanted embryonic stem cells are exposed to immune reactions similar to those acting on organ transplants, hence immunosuppression of the recipient is generally required. It is, however, possible to obtain embryonic stem cells that are genetically identical to the patient's own cells by means of therapeutic cloning techniques. The nucleus from a somatic cell is transferred into an egg after removal of the egg's own genetic material. Under specific condition the egg will use genetic information from the somatic cell in organising the formation of a blastocyst which in turn generates embryonic stem cells. These cells have a genetic composition identical to that of the patient and are suitable for stem cell therapy.

Takanashi, M., H. Mochizuki, et al. (2001). "Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP)." 7(4): 311-314.
Autosomal recessive juvenile parkinsonism (ARJP) is a distinct clinical and genetic entity characterized by highly selective neuronal death in the substantia nigra (SN) and locus coeruleus neurons without Lewy body formation. The mechanism of neuronal death of ARJP is still unknown. Our study demonstrated that iron staining was more intense in ARJP than in both controls and sporadic Parkinson's disease (PD), and there were differences in the pattern of distribution of iron staining between ARJP and PD. In addition neurites of SN in ARJP showed intense iron staining. Thus, we postulate that oxidative stress may play an important role in the neurodegeneration that occurs in ARJP.

Tan, E. K., S. Nagamitsu, et al. (2001). "Alcohol dehydrogenase polymorphism and Parkinson's disease." Neurosci Lett 305(1): 70-2.
A particular alcohol dehydrogenase (ADH) polymorphism (allele A1) in the promoter region of the gene has been recently demonstrated to be associated with increased risk of Parkinson's disease (PD). In a case control study, we examine frequencies of ADH A1 allele in 100 PD patients (i.e. 200 alleles), 100 diseased controls (i.e. 200 alleles), and 194 healthy controls (i.e. 388 alleles). In addition, we study possible association of a combined non-amyloid component of plaque (NACP-Rep 1) allele and ADH A1 allele with risk of PD. There was no statistical significance of the frequencies of ADH A1 allele between PD patients 12/200 (6%), diseased controls 13/200 (6.5%), and healthy controls 20/388 (5.2%). No strong evidence of an association was found between ADH A1 allele and PD susceptibility in our study patients. There was also no suggestion of linkage disequilibrium between NACP-Rep 1 and ADH A1 alleles.

Tan, S., N. Somia, et al. (2001). "Regulation of antioxidant metabolism by translation initiation factor 2alpha." J Cell Biol 152(5): 997-1006.
Oxidative stress and highly specific decreases in glutathione (GSH) are associated with nerve cell death in Parkinson's disease. Using an experimental nerve cell model for oxidative stress and an expression cloning strategy, a gene involved in oxidative stress-induced programmed cell death was identified which both mediates the cell death program and regulates GSH levels. Two stress-resistant clones were isolated which contain antisense gene fragments of the translation initiation factor (eIF)2alpha and express a low amount of eIF2alpha. Sensitivity is restored when the clones are transfected with full-length eIF2alpha; transfection of wild-type cells with the truncated eIF2alpha gene confers resistance. The phosphorylation of eIF2alpha also results in resistance to oxidative stress. In wild-type cells, oxidative stress results in rapid GSH depletion, a large increase in peroxide levels, and an influx of Ca(2+). In contrast, the resistant clones maintain high GSH levels and show no elevation in peroxides or Ca(2+) when stressed, and the GSH synthetic enzyme gamma-glutamyl cysteine synthetase (gammaGCS) is elevated. The change in gammaGCS is regulated by a translational mechanism. Therefore, eIF2alpha is a critical regulatory factor in the response of nerve cells to oxidative stress and in the control of the major intracellular antioxidant, GSH, and may play a central role in the many neurodegenerative diseases associated with oxidative stress.

Tang, K., M. J. Low, et al. (2001). "Dopamine-dependent synaptic plasticity in striatum during in vivo development." Proc Natl Acad Sci U S A 98(3): 1255-60.
The neurotransmitters dopamine (DA) and glutamate in the striatum play key roles in movement and cognition, and they are implicated in disorders of the basal ganglia such as Parkinson's disease. Excitatory synapses in striatum undergo a form of developmental plasticity characterized by a decrease in glutamate release probability. Here we demonstrate that this form of synaptic plasticity is DA and DA D2 receptor dependent. Analysis of spontaneous synaptic responses indicates that a presynaptic mechanism involving inhibition of neurotransmitter release underlies the developmental plasticity. We suggest that a major role of DA in the striatum is to initiate mechanisms that regulate the efficacy of excitatory striatal synapses, producing a decrease in glutamate release.

Tanner, C. M., S. M. Goldman, et al. (2001). "Essential tremor in twins: An assessment of genetic vs environmental determinants of etiology." Neurology 57(8): 1389-91.
OBJECTIVE: - To determine the relative contribution of genetics and environment to essential tremor using a twin study method. METHODS: - Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. RESULTS: - A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). CONCLUSION: - This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

Theofilopoulos, S., J. Goggi, et al. (2001). "Parallel induction of the formation of dopamine and its metabolites with induction of tyrosine hydroxylase expression in foetal rat and human cerebral cortical cells by brain-derived neurotrophic factor and glial-cell derived neurotrophic factor." Brain Res Dev Brain Res 127(2): 111-22.
Brain-derived neurotrophic factor (BDNF; 50 ng/ml), dopamine (DA; 10 microM) and forskolin (Fsk; 10 microM) have previously been shown by this and other laboratories to induce the tyrosine hydroxylase (TH) enzyme in foetal human and rat cerebral cortex during specified sensitive developmental periods. In the present study, these findings were extended for human and rat cells by showing that the induced TH+ cells also produce dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). In addition to this, TH induction and DA plus DOPAC production was observed in foetal human and rat cerebral cortex by using glial-cell derived neurotrophic factor (GDNF) in place of BDNF. The degree of induction by GDNF (1-10 ng/ml) was similar to that produced by BDNF and did not increase further when the two neurotrophic factors were used together. The time-course of induction in human cultures was followed: GDNF was found to cause a more rapid induction process than BDNF during the first 2 weeks. However the degree of induction after 3 weeks was the same for both neurotrophic factors. Inhibitors of transcription (actinomycin D) or of translation (cycloheximide) eliminated all the increase in DA+DOPAC contents elicited by these compounds, indicating that de novo transcription and translation were required for increased expression of the TH and other related enzymes. The intracellular pathways by which these molecules exert this dopaminergic phenotype induction effect are discussed. This study indicates a new source of dopaminergic brain tissue for use as transplants to neurosurgically treat Parkinson's disease patients.

Tilgner, J., B. Volk, et al. (2001). "Continuous interleukin-6 application in vivo via macroencapsulation of interleukin-6-expressing COS-7 cells induces massive gliosis." Glia 35(3): 234-45.
The inflammatory cytokine interleukin-6 (IL-6) was found in senile plaques of Alzheimer's patients and might be involved in the pathology of Parkinson's disease and multiple sclerosis. Interestingly, an astocytosis is also found in these neurodegenerative disorders. To evaluate the direct effects of IL-6 in vivo on glial cells, we created a new in vivo model. IL-6 and mock-transfected (control group) COS-7 cells were encapsulated in a poly-acryl-nitril membrane for implantation into the rat striatum. Afterward, the host immune reaction to the membrane without encapsulated cells and the biological action of IL-6-producing capsules was evaluated. Animals with an implanted membrane without cells showed a moderate astrocytosis 5 days after the operation. Furthermore, microglia and T-cells could be detected and after 30 days the astrocytosis decreased to a small layer around the membrane. In comparison to the control group, which received a sham operation, our results demonstrate that the response of glial cells is caused by the mechanical damage of the surgical procedure itself rather than due to the introduced membrane material. In contrast, we found a massive proliferation and activation of astrocytes and microglia after 10 days by IL-6-secreting capsules, indicating that IL-6 is involved in the induction of gliosis. Control animals that received encapsulated mock-transfected COS-7 cells showed only a weak response. These data point to an involvement of IL-6 in the proliferation and activation of glial cells as seen in neurodegenerative disorders.

Tomonaga, K., T. Kobayashi, et al. (2001). "[The neuropathogenesis of Borna disease virus infection]." Nippon Rinsho 59(8): 1605-13.
Borna disease virus(BDV) is a noncytolytic, neurotropic RNA virus that causes a disease of the central nervous system(CNS) in several vertebrate species, including horses, sheep, cats and ostriches. Epidemiological studies using peripheral blood or brain samples revealed that BDV can infect humans and that it may be related with certain neuropsychiatric disorders. The unique genetic and biological properties of BDV indicate that BDV develops a persistent infection in the CNS. Furthermore, a line of recent evidences suggests that BDV infection causes direct effects on brain functions in the absence of immunopathology-related brain damage. In this review, we discuss about recent data regarding neuropathogenesis of BDV infections in animals and humans.

Touchman, J. W., A. Dehejia, et al. (2001). "Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element." Genome Res 11(1): 78-86.
The human alpha-synuclein gene (SNCA) encodes a presynaptic nerve terminal protein that was originally identified as a precursor of the non-beta-amyloid component of Alzheimer's disease plaques. More recently, mutations in SNCA have been identified in some cases of familial Parkinson's disease, presenting numerous new areas of investigation for this important disease. Molecular studies would benefit from detailed information about the long-range sequence context of SNCA. To that end, we have established the complete genomic sequence of the chromosomal regions containing the human and mouse alpha-synuclein genes, with the objective of using the resulting sequence information to identify conserved regions of biological importance through comparative sequence analysis. These efforts have yielded approximately 146 and approximately 119 kb of high-accuracy human and mouse genomic sequence, respectively, revealing the precise genetic architecture of the alpha-synuclein gene in both species. A simple repeat element upstream of SNCA/Snca has been identified and shown to be necessary for normal expression in transient transfection assays using a luciferase reporter construct. Together, these studies provide valuable data that should facilitate more detailed analysis of this medically important gene.

Valente, E. M., A. R. Bentivoglio, et al. (2001). "Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36." Am J Hum Genet 68(4): 895-900.
The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.

van Duijn, C. M., M. C. Dekker, et al. (2001). "Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36." Am J Hum Genet 69(3): 629-34.
Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

Vaughan, J. R., M. B. Davis, et al. (2001). "Genetics of Parkinsonism: a review." Ann Hum Genet 65(Pt 2): 111-26.
Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

Veech, R. L., B. Chance, et al. (2001). "Ketone bodies, potential therapeutic uses." IUBMB Life 51(4): 241-7.
Ketosis, meaning elevation of D-beta-hydroxybutyrate (R-3hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-beta-hydroxybutyrate (abbreviated "betaOHB") may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from betaOHB include an increased energy of ATP hydrolysis (deltaG') and its linked ionic gradients. This may be significant in drug-resistant epilepsy and in injury and anoxic states. The ability of betaOHB to oxidize co-enzyme Q and reduce NADP+ may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of betaOHB to 2-5 mmol may require synthetic esters or polymers of betaOHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves.

Wang, J., Z. L. Liu, et al. (2001). "Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease." Neurosci Lett 308(1): 21-4.
Motor fluctuations are the most common complication of levodopa therapy for Parkinson's disease (PD). Genetic factors could play a role in determining the occurrence of motor fluctuations. To investigate whether dopamine receptor D5 (DRD5) T978C polymorphism is associated with the risk of developing motor fluctuations in PD, we studied this polymorphism in a case-control study of 120 subjects with sporadic PD and 110 control subjects. We found that the overall allelic and genotypic frequencies did not differ significantly between patients with PD and control subjects (all P>0.7), and between motor fluctuators (n=50) and non-motor fluctuators (n=50) (all P>0.8). It suggests that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations in PD. Therefore, other polymorphisms that alter the expression of the dopamine receptors should be further studied.

Wang, Y. C., H. C. Liu, et al. (2001). "Genetic association analysis of alpha-1-antichymotrypsin polymorphism in Parkinson's disease." Eur Neurol 45(4): 254-6.
alpha(1)-Antichymotrypsin (ACT) gene has been suggested as a susceptibility factor for Parkinson's disease (PD) and might be related to the onset of PD. We replicated these findings in a Chinese population. The results demonstrated that the ACT genotypic and allelic distributions showed no significant differences between the PD patient and the control groups. The age at onset was younger in the heterozygotes than in the homozygotes (p = 0.042). We suggest that the ACT polymorphism might play some role in the pathogenesis of PD, especially in the onset. Copyright 2001 S. Karger AG, Basel

Weissig, V. and V. P. Torchilin (2001). "Towards mitochondrial gene therapy: DQAsomes as a strategy." J Drug Target 9(1): 1-13.
Mitochondrial dysfunction is a cause, or major contributing factor in the development, of degenerative diseases, aging, cancer, many cases of Alzheimer's and Parkinson's disease and Type II diabetes (D. C. Wallace, Science 283, 1482-1488, 1999). Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment for the vast majority of patients available. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. However, mitochondrial gene therapy has been elusive, due to the lack of any mitochondria-specific transfection vector. We review here the current state of the development of mitochondrial DNA delivery systems. In particular, we are summarizing our own efforts in exploring the mitochondriotropic properties of dequalinium, a cationic bolaamphiphile with delocalized charge centers, for the design of a vector suited for the transport of DNA to mitochondria in living cells.

Woo, S. I., J. W. Kim, et al. (2001). "CYP2D6*4 polymorphism is not associated with Parkinson's disease and has no protective role against Alzheimer's disease in the Korean population." Psychiatry Clin Neurosci 55(4): 373-7.
CYP2D6*4 polymorphism is reported to be associated with Parkinson's disease (PD) and to have protective role against Alzheimer's disease (AD). Such findings are not extensively studied in the Oriental population, especially Koreans. The effects of CYP2D6*4 polymorphism on AD and PD were investigated by polymerase chain reaction-restriction fragment length polymorphism in Korean subjects. Heterozygous mutant allele was found in four of 93 patients with PD, 0 of 32 patients with AD and one of 121 control subjects (59 stroke, 59 normal controls and four other psychiatric disorders), but no homozygous mutant allele was found. There were no statistically significant differences between the AD group and controls, and between the PD group and controls. In conclusion, we suggest that CYP2D6*4 polymorphism does not confer susceptibility to PD in the Korean population. Also, due to such a rare occurrence of the CYP2D6*4 polymorphism, we can not confirm the protective role of the polymorphism against AD in the Korean population.

Woodward, G. (2001). "Autism and Parkinson's disease." Med Hypotheses 56(2): 246-9.
The pathogenesis of Parkinson's disease, a neurodegenerative disorder, is multifaceted, having a variety of genetic and environmental factors. There is considerable evidence to support the role of toxins, particularly pesticides and herbicides, in at least some of those affected (presumably, mostly the genetically vulnerable). The pathogenesis of autism is no less complex, but little is known about the potential role of toxins for autism, a neurodevelopmental disorder. The incidence of autism appears to be rising, and early exposure to synthetic chemicals is one suspect for this rise. Impaired detoxification of certain chemicals may be common to autism and Parkinson's disease. Further study of environmental influences for either disorder may lead to important insights regarding causation for both, and perhaps for other neurodegenerative and neurodevelopmental disorders as well.

Wu, R. M., C. W. Cheng, et al. (2001). "The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese." Neurology 56(3): 375-82.
OBJECTIVE: Reports suggest that catechol-O-methyltransferase (COMT(L/L)) (Val(158)/Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. METHODS: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. chi(2), OR, and Fisher's exact tests were used to compare differences in allelic frequencies and genotypes. RESULTS: The MAOB G genotype (G in men and G:/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMT(L) and MAOB G genotypes. CONCLUSIONS: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMT(L) genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.