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

Mutations of the alpha -synuclein gene have been identified in autosomal dominant Parkinson's disease (PD), Transgenic mice overexpressing wild-type human alpha -synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum, To study the mechanism of action through which mutant alpha -synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha -synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha -synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha -synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha -synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.