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.

Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp Med Biol 487: 147-67.

Bauer, M., M. Meyer, et al. (2001). "Liposome-mediated gene transfer to fetal human ventral mesencephalic explant cultures." Neurosci Lett 308(3): 169-72.
The feasibility of non-viral gene transfer using liposomes is described for human fetal nigral tissue. Ventral mesencephalic explants from 6 to 12 week old fetuses were grown as free-floating roller tube cultures. For the transfection, a vector coding for beta-galactosidase driven by the Rous Sarcoma Virus promoter was used. The developmental stage of the human tissue, time in vitro and the amount of vector DNA used significantly influenced the transfection efficiency. Optimal transfection results were obtained with tissue from a 10 week old fetus, cultured for 4 days and transfected with mixtures containing 4 microg vector DNA. Histological analysis suggested that a specific population of ventral mesencephalic precursor cells were the target for the gene transfer. This finding might have implications for gene delivery and cell replacement strategies in Parkinson's disease.

Beal, M. F. (2001). "Experimental models of Parkinson's disease." Nat Rev Neurosci 2(5): 325-34.
Research into the pathogenesis of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that causes parkinsonism in man. More recently, the identification of alpha-synuclein mutations as a rare cause of Parkinson's disease has led to the development of alpha-synuclein transgenic mice and Drosophila. Here, I discuss the merits and limitations of these different animal models in our attempts to understand the physiology of Parkinson's disease and to develop new therapies.

Beal, M. F. and P. Hantraye (2001). "Novel therapies in the search for a cure for Huntington's disease." Proc Natl Acad Sci U S A 98(1): 3-4.

Begley, S. (2001). "IV. Genes, cells, drugs. Cures for the future. Fountains of youth." Newsweek 138(11A): 84-6.

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.

Berciano, J. (2001). "[Genetics in Parkinson's disease: toward a new nosological era]." Med Clin (Barc) 116(16): 614-6.

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.

Bezard, E., P. Ravenscroft, et al. (2001). "Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine monkeys." Neurobiol Dis 8(2): 343-50.
GABA and enkephalin-utilizing efferents from the striatum to the external segment of the pallidal complex (GPe) are thought to be overactive in Parkinson's disease (PD). This overactivity is generally held to play a major role in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkephalin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian motor disabilities, the present study assessed PPE-A mRNA expression and striatal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monkeys showing a marked DA depletion (56%). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals, supports our initial hypothesis of such an upregulation occurring before the appearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings question the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway. Copyright 2001 Academic Press.

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.

Bonifati, V. (2001). "Monogenic Parkinsonisms and the genetics of Parkinson's disease." Funct Neurol 16(1): 35-44.

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.

Boulu, R. G., C. Mesenge, et al. (2001). "[Neuronal death: potential role of the nuclear enzyme, poly (ADP-ribose) polymerase]." Bull Acad Natl Med 185(3): 555-63; discussion 564-5.
Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is known as a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. It is also called poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADRT). In physiological conditions, PARP plays an important role in maintaining genomic stability. However, for several pathological situations, which include massive DNA injury (brain ischemia for example), excessive activation of PARP can deplete stores of nicotinamide adenine dinucleotide (NAD+), the PARP substrate, which, with the subsequent ATP depletion, leads to cell death. PARP activation appears to play a major role in neuronal death induced by cerebral ischemia, traumatic brain injury, Parkinson disease and other pathologies. PARP inhibitors (3-aminobenzamide and other compounds) and PARP gene deletion induced dramatic neuroprotection in experimental animals (rats, mice). Accordingly, these data suggest that PARP inhibitors could provide a novel therapeutic approach in a wide range of neurodegenerative disorders including cerebral ischemia and traumatic brain injury.

Brattstrom, L. (2001). "Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD." Neurology 56(2): 281; discussion 281-2.

Brevig, T., M. Meyer, et al. (2001). "Xenotransplantation for brain repair: reduction of porcine donor tissue immunogenicity by treatment with anti-Gal antibodies and complement." Transplantation 72(2): 190-6.
BACKGROUND: Transplantation of embryonic neural tissue is a potential treatment for Parkinson's disease. Because human donor material is in short supply, porcine xenografts are considered a useful alternative. Current immunosuppressive therapies fail, however, to protect intracerebral neural xenografts from host CD4 T lymphocytes. To reduce the immunogenicity of porcine donor tissue, we attempted to remove microglial cells with antibodies against the alpha-galactosyl epitope (Galalpha1,3Galbeta1,4GlcNAc-R), or anti-Gal, and complement, and studied whether this pretreatment can reduce direct and indirect T-cell responses to the tissue. METHODS: Brain tissue from 27-day-old pig embryos was dissociated and treated with human anti-Gal and rabbit complement. The microglial content was analyzed by flow cytometry. [3H]thymidine incorporation in cocultures of the brain cells and purified human CD4 T cells was used to determine direct T-cell responses. Indirect T-cell responses were studied by grafting pretreated and control-pretreated (no anti-Gal) nigral tissue into the lesioned striatum of immunocompetent rats with 6-hydroxydopamine-induced hemiparkinsonism. Amphetamine-induced circling behavior was used to measure graft function. RESULTS: Anti-Gal and complement reduced the microglial content to 11-24% of control and abolished the ability of the brain cells to induce human CD4 T-cell proliferation. Pretreated nigral tissue reduced hemiparkinsonism by more than 50% in five of eight rats at some point during the 10-week follow-up. Rats receiving control-pretreated nigral tissue did not display this degree of improvement. CONCLUSIONS: Pretreatment with anti-Gal and complement can reduce the immunogenicity of porcine neural tissue, and might, therefore, be a valuable alternative or supplement to immunosuppression in neural xenotransplantation.

Brooksbank, C. (2001). "Protein degradation: Parkin finds a partner and a victim." Nat Rev Mol Cell Biol 2(1): 4-5.

Buervenich, S., F. Xiang, et al. (2001). "Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA) gene and an investigation of their possible associations with Parkinson disease, schizophrenia, and manic depression." Hum Mutat 17(5): 435-6.
We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction fragment length polymorphism) detection and investigated association with neurological or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent association study, frequencies of the identified polymorphisms in Parkinson and schizophrenia patients were compared with frequencies in the normal population. No statistically significant association was found in our material. The 16-bp microdeletion polymorphism was present in a family with multiple cases of unipolar or bipolar depressive disorder. Using this polymorphism as marker, cosegregation with the phenotype was observed in the majority of individuals. Copyright 2001 Wiley-Liss, Inc.