Abe, K. and H. Saito (2001). "Effects of basic fibroblast growth factor on central nervous system functions." Pharmacol Res 43(4): 307-12.
Basic fibroblast growth factor (bFGF), initially identified as mitogens with prominent angiogenic properties, is now recognized as multifunctional growth factors with notable actions on neuronal cells. bFGF promotes the survival and neurite growth of brain neurons in vitro and in vivo, suggesting that it functions as a neurotrophic factor. This effect of bFGF could be beneficial for improving the survival of grafted neurons in transplantation. Furthermore, bFGF acutely modulates synaptic transmission in the hippocampus, suggesting that it has a role like a neurotransmitter or neuromodulator. In this article, we make a brief review of multiple biological activities of bFGF for brain neurons and discuss its potential usefulness for the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. Copyright 2001 Academic Press.

Abell, C. W. and S. W. Kwan (2001). "Molecular characterization of monoamine oxidases A and B." Prog Nucleic Acid Res Mol Biol 65: 129-56.
Monoamine oxidase A and B (MAO A and B) are the major neurotransmitter-degrading enzymes in the central nervous system and in peripheral tissues. MAO A and B cDNAs from human, rat, and bovine species have been cloned and their deduced amino acid sequences compared. Comparison of A and B forms of the enzyme shows approximately 70% sequence identity, whereas comparison of the A or B forms across species reveals a higher sequence identity of 87%. Within these sequences, several functional regions have been identified that contain crucial amino acid residues participating in flavin adenine dinucleotide (FAD) or substrate binding. These include a dinucleotide-binding site, a second FAD-binding site, a fingerprint site, the FAD covalent-binding site, an active site, and the membrane-anchoring site. The specific residues that play a role in FAD or substrate binding were identified by comparing sequences in wild-type and variants of MAO with those in soluble flavoproteins of known structures. The genes that encode MAO A and B are closely aligned on the X chromosome (Xp11.23), and have identical exon-intron organization. Immunocytochemical localization studies of MAO A and B in primate brain showed distribution in distinct neurons with diverse physiological functions. A defective MAO A gene has been reported to associate with abnormal aggressive behavior. A deleterious role played by MAO B is the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a proneurotoxin that can cause a parkinsonian syndrome in mammals. Deprenyl, an inhibitor of MAO B, has been used for the treatment of early-stage Parkinson's disease and provides protection of neurons from age-related decay.

Akhmedova, S. N., A. K. Yakimovsky, et al. (2001). "Paraoxonase 1 Met--Leu 54 polymorphism is associated with Parkinson's disease." J Neurol Sci 184(2): 179-82.
Two up-to-date known paraoxonase 1 (PON1) polymorphisms (Gln--Arg 191 and Leu--Met 54) affect the hydrolysis of toxic oxons and might intensify effects of pollutants, organophosphates and other environmental chemicals in development of Parkinson's disease (PD). We reported previously that PON1 G1n--Arg 191 polymorphism did not influence on the susceptibility to PD. In the present study we have investigated the PON1 Leu--Met 54 polymorphism in 117 patients with sporadic idiopathic PD. A new approach for Leu--Met 54 polymorphism genotyping has been developed. We have showed the frequency of the Met 54 allele of PON1 to be significantly increased in patients with PD compared with the controls (chi(2)=8.63, df=1, P<0.003). The relative risk of PD in the Met 54 allele carriers has been estimated to be 2.3 fold higher than in homozygotes for the L allele. Moreover it appeared to be even 5.15 higher in the subgroup of patients with early-onset PD. We suggest that the Met 54 allele may be considered to be an independent risk factor for PD. This mutation could probably cause PON1 impaired metabolism of environmental neurotoxins and might be responsible for neurodegeneration.

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.

Anichtchik, O. V., N. Peitsaro, et al. (2001). "Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease." Neurobiol Dis 8(4): 707-16.
Parkinson's disease (PD) is a brain degenerative disorder with unknown etiology, and specific degeneration of mesencephalic dopaminergic cells is a morphological manifestation of the disease. The central histaminergic system appears to be activated in PD, since the histaminergic innervation is increased in the substantia nigra. The aim of the present study was to investigate the expression and function of histamine H(3) receptors in PD, using receptor mRNA in situ hybridization with oligonucleotide probes, receptor binding assay with a specific radioactive agonist, and GTP-gamma-[(35)S]-binding assay as a tool to study the activation of the receptor G-protein. H(3) receptor binding sites were detected using N-alpha-methylhistamine autoradiography in the basal ganglia and cortex, being most abundant in the substantia nigra and striatum. In PD substantia nigra we detected an increase of the receptor binding density. In situ hybridization study of the receptor mRNA revealed prominent sites of H(3) receptor synthesis in the putamen, cortex, and globus pallidus, whereas very low mRNA expression was seen in the substantia nigra. In the PD pallidum externum, H(3) receptor mRNA expression was elevated as compared with the normal brains. GTP-gamma-[(35)S]-binding assay did not reveal any significant difference between PD and normal brains, although the density values in PD substantia nigra tended to be lower than in the normal brain, and density values in PD striatum were higher. The dopaminergic neurons did not express significant amount of H(3) receptor mRNA, suggesting that the effects of H(3) receptor-mediated modulation of dopamine release are indirect. Our data indicates modulation of the histamine H(3) receptor in PD at the level of the mRNA expression in the striatum and receptor density in the substantia nigra. The receptor activity seems to be unchanged or decreased, as revealed by GTP-gamma-[(35)S]-binding assay. Modulation of the histamine H(3) receptor may influence the activity of other neurotransmitter systems, e.g., the GABAergic one, in the substantia nigra.

Aomi, Y., C. S. Chen, et al. (2001). "Cytoplasmic transfer of platelet mtDNA from elderly patients with Parkinson's disease to mtDNA-less HeLa cells restores complete mitochondrial respiratory function." Biochem Biophys Res Commun 280(1): 265-73.
For determination of whether platelet mtDNA in patients with Parkinson's disease (PD) possesses some lesions to reduce respiratory enzyme activities, platelet mtDNA was transferred into mtDNA-less (rho0) HeLa cells from aged PD patients and age-matched normal subjects, since their activities were controlled by both mitochondrial and nuclear genomes. The resultant mtDNA-repopulated cybrid clones containing the HeLa nuclear genome as a common background were used for comparison of respiratory enzyme activities. Remarkable variations of the enzyme activities were observed in the cybrid clones, irrespective of whether their mtDNA was transferred from normal subjects or PD patients, and some of them showed 20% reduction of average activities. Thus, the mtDNA mutations responsible for inducing 20% reduction should be polymorphic rather than pathogenic. On the other hand, pathogenic control cybrid clones possessing mtDNA mutations from patients with mitochondrial disorders showed significant and specific decline of respiratory enzyme complex I activity beyond the normal range of the variations. These observations warrant reassessment of the conventional concept that complex I activity in platelets of PD patients is defective due to mtDNA mutations. Copyright 2001 Academic Press.

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.