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Human Molecular Genetics Advance Access published online on October 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi396
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 15, 2005
Revised October 13, 2005
Accepted October 13, 2005

Article

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

Wanli W. Smith 1, Haibing Jiang 1, Zhong Pei 1, Yuji Tanaka 2, Hokuto Morita 3, Akira Sawa 4, Valina L. Dawson 5, Ted M. Dawson 6, and Christopher A. Ross 7*

1 Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
2 Department of Neuropsychiatry, Okayama University School of Medicine, Okayama, Japan 7008558
3 Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
4 Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
5 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Institute For Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
6 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Institute For Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
7 Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205; Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287

* To whom correspondence should be addressed.
Christopher A. Ross, E-mail: caross{at}jhu.edu


  Abstract

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 caspase-3 activities. Cell death was partially blocked by cyclosporine A (an inhibitor of the mitochondrial permeability transition 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 endoplasmic reticulum stress and mitochondrial dysfunction contribute to A53T alpha-synuclein-induced cell death. This study sheds light into the pathogenesis of (lpha-synuclein cellular toxicity in PD, and provides a cell model for screening PD therapeutic agents.


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