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J. Biol. Chem., Vol. 280, Issue 40, 34025-34032, October 7, 2005

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Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations^*

Agnes Petit, Toshitaka Kawarai, Erwan Paitel, Nobuo Sanjo, Mary Maj, Michael Scheid¶, Fusheng Chen, Yongjun Gu, Hiroshi Hasegawa, Shabnam Salehi-Rad, Linda Wang, Ekaterina Rogaeva, Paul Fraser, Brian Robinson, Peter St George-Hyslop1, and Anurag Tandon

From the Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), University of Toronto, Toronto, Ontario M5S 3H2, Canada, the Metabolic Research Programme, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and the ^¶Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada

Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations.

Received for publication, May 10, 2005 , and in revised form, July 29, 2005.

^* This work was supported by grants from the Canadian Institutes of Health Research, the Howard Hughes Medical Institute, Canadian Institutes of Health Research, Japan Science and Technology Trust, the Jack Clarke Chair, the Michael J Fox Foundation, the Scottish Rite Charitable Foundation of Canada, the Parkinson Society of Canada, the Alzheimer Society of Ontario, and the Canada Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent W., Toronto, Ontario, Canada M5S 3H2. Tel.: 416-978-7460; Fax: 416-978-1878; E-mail: p.hyslop{at}utoronto.ca.

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