Human Molecular Genetics, 2001, Vol. 10, No. 9 919-926
© 2001 Oxford University Press
Inducible expression of mutant 
-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis
1Department of Psychiatry, 2Department of Neuroscience, 3Department of Neurology, 4Department of Physiology and 5Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA, 6Departamento de Anatomia, Universidade Federal do Rio de Janeiro, Ilha do Fundao, Brazil and 7Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although mutations in 
-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD. We established inducible PC12 cell lines in which wild-type or mutant -synuclein can be de-repressed by removing doxycycline. Differentiated PC12 cell lines expressing mutant -synuclein showed decreased activity of proteasomes without direct toxicity. Cells expressing mutant -synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A. These data suggest that expression of mutant -synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.
+ To whom correspondence should be addressed at: Department of Psychiatry, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 618, Baltimore, MD 21205-2196, USA. Tel: +1 410 614 0011; Fax: +1 410 614 0013; Email: caross@jhu.edu
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