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Human Molecular Genetics, 2000, Vol. 9, No. 18 2683-2689
© 2000 Oxford University Press

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

Sarah J. Tabrizi1,+, Michael Orth+,1, J. Max Wilkinson2, Jan-Willem Taanman1, Thomas T. Warner1, J. Mark Cooper1 and Anthony H.V. Schapira1,3,§

1University Department of Clinical Neurosciences, 2Renal Unit, Royal Free and University College Medical School and 3Institute of Neurology, University College London, London NW3 2PF, UK

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.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +44 207 830 2012; Fax: +44 207 431 1577; Email: schapira@rfhsm.ac.uk


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