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Human Molecular Genetics Advance Access originally published online on October 20, 2005
Human Molecular Genetics 2005 14(24):3801-3811; doi:10.1093/hmg/ddi396
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity

Wanli W. Smith1, Haibing Jiang1, Zhong Pei1, Yuji Tanaka7, Hokuto Morita1,3, Akira Sawa1,3,6, Valina L. Dawson2,3,4,5,6, Ted M. Dawson2,3,5,6 and Christopher A. Ross1,2,3,6,*

1Division of Neurobiology, Department of Psychiatry, 2Department of Neurology, 3Department of Neuroscience, 4Department of Physiology, 5Institute for Cell Engineering and 6Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 7Department of Neuropsychiatry, Okayama University School of Medicine, Okayama 7008558, Japan

* To whom correspondence should be addressed at: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA. Tel: +1 4106140010; Fax: +1 4106140013; Email: caross{at}jhu.edu

Received August 15, 2005; Accepted October 13, 2005

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and mutations in alpha-synuclein cause autosomal-dominant hereditary PD. Here, we generated A53T mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular ROS level and caused up to ~40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities. Cell death was partially blocked by cyclosporine A [an inhibitor of the mitochondrial permeability transition (MPT) process], z-VAD (a pan-caspase inhibitor) and inhibitors of caspase-9 and -3 but not by a caspase-8 inhibitor. Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 activity. RNA interference to knock down caspase-12 levels or salubrinal (an ER stress inhibitor) partially protected against cell death and further reduced A53T toxicity after treatment with z-VAD. Our results indicate that both ER stress and mitochondrial dysfunction contribute to A53T alpha-synuclein-induced cell death. This study sheds light into the pathogenesis of alpha-synuclein cellular toxicity in PD and provides a cell model for screening PD therapeutic agents.


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