alpha-synuclein and Parkinson's disease: Selective neurodegenerative effect of alpha-synuclein fragment on dopaminergic neurons in vitro and in vivo

Missense mutations in the alpha-synuclein gene were associated with a famil ial Parkinson's disease, and alpha-synuclein is a major component of Lewy b odies, the intracellular inclusions that neuropathologically characterize P arkinson's disease. We investigated the neurotoxic activity of the nonamylo id component (NAC) of senile plaque, the fibrillogenic fragment (61-95) of alpha-synuclein, in vitro and in vivo. Rat primary mesencephalic neurons we re exposed for 6 days to low concentrations of preaggregated NAC (0.5-10.0 mu M). The number of dopaminergic neurons and dopamine content were both re duced with no effect on the general viability of the cells. At higher conce ntrations (25-100 mu M), the neurotoxic effect of NAC was extended to all n eurons. Preaggregated NAC was also toxic on a PC12 dopaminergic cell line d ifferentiated with nerve growth factor. The intracellular localization of N AC has been identified by the exposure of neuronal cells to fluorescent pep tide 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 alph a-synuclein in the pathogenesis of Parkinson's disease.