Missense mutations in the α-synuclein gene were associated with a familial Parkinson's disease, and α-synuclein is a major component of Lewy bodies, the intracellular inclusions that neuropathologically characterize Parkinson's disease. We investigated the neurotoxic activity of the nonamyloid component (NAC) of senile plaque, the fibrillogenic fragment (61- 95) of α-synuclein, in vitro and in vivo. Rat primary mesencephalic neurons were exposed for 6 days to low concentrations of preaggregated NAC (0.5-10.0 μM). The number of dopaminergic neurons and dopamine content were both reduced with no effect on the general viability of the cells. At higher concentrations (25-100 μM), the neurotoxic effect of NAC was extended to all neurons. Preaggregated NAC was also toxic on a PC12 dopaminergic cell line differentiated with nerve growth factor. The intracellular localization of NAC has been identified by the exposure of neuronal cells to fluorescent peptide. In vivo application of aggregated NAC in the substantia nigra induced loss of dopaminergic neurons. Our data illustrate the selective neurotoxic effect of NAC for dopaminergic neurons and support the central role of α-synuclein in the pathogenesis of Parkinson's disease.
|Number of pages||9|
|Journal||Annals of Neurology|
|Publication status||Published - 2000|
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