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.
Nielsen, M. S., H. Vorum, et al. (2001). "Ca2+ binding to alpha-synuclein
regulates ligand binding and oligomerization." J Biol Chem 276(25):
22680-4.
alpha-Synuclein is a protein normally involved in presynaptic vesicle
homeostasis. It participates in the development of Parkinson's disease, in which
the nerve cell lesions, Lewy bodies, accumulate alpha-synuclein filaments. The
synaptic neurotransmitter release is primarily dependent on Ca(2+)-regulated
processes. A microdialysis technique was applied showing that alpha-synuclein
binds Ca(2+) with an IC(50) of about 2-300 microm and in a reaction uninhibited
by a 50-fold excess of Mg(2+). The Ca(2+)-binding site consists of a novel
C-terminally localized acidic 32-amino acid domain also present in the homologue
beta-synuclein, as shown by Ca(2+) binding to truncated recombinant and
synthetic alpha-synuclein peptides. Ca(2+) binding affects the functional
properties of alpha-synuclein. First, the ligand binding of (125)I-labeled
bovine microtubule-associated protein 1A is stimulated by Ca(2+) ions in the
1-500 microm range and is dependent on an intact Ca(2+) binding site in alpha-synuclein.
Second, the Ca(2+) binding stimulates the proportion of
(125)I-alpha-synuclein-containing oligomers. This suggests that Ca(2+) ions may
both participate in normal alpha-synuclein functions in the nerve terminal and
exercise pathological effects involved in the formation of Lewy bodies.