Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity

Mutations of the alpha -synuclein gene have been identified in autosomal do minant Parkinson's disease (PD), Transgenic mice overexpressing wild-type h uman alpha -synuclein develop motor impairments, intraneuronal inclusions a nd loss of dopaminergic terminals in the striatum, To study the mechanism o f action through which mutant alpha -synuclein toxicity is mediated, we hav e generated stable, inducible cell models expressing wild-type or PD-associ ated mutant (G209A) alpha -synuclein in human-derived HEK293 cells. Increas ed expression of either wild-type or mutant alpha -synuclein resulted in th e formation of cytoplasmic aggregates which were associated with the vesicu lar (including monoaminergic) compartment. Expression of mutant alpha -synu clein induced a significant increase in sensitivity to dopamine toxicity co mpared with the wild-type protein expression. These results provide an expl anation for the preferential dopaminergic neuronal degeneration seen in bot h the PD G209A mutant alpha -synuclein families and suggest that similar me chanisms may underlie or contribute to cell death in sporadic PD.