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

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Abstract
Mutations of the α-synuclein gene have been identified in autosomal dominant Parkinson’s disease (PD). Transgenic mice overexpressing wild-type human α-synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum. To study the mechanism of action through which mutant α-synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) α-synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant α-synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant α-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 α-synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.

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