Expression of mutant [alpha]-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 degenera-tion 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.