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J. Biol. Chem., Vol. 279, Issue 9, 8506-8515, February 27, 2004

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Familial Parkinson's Disease-associated L166P Mutation Disrupts DJ-1 Protein Folding and Function^*

James A. Olzmann, Keith Brown, Keith D. Wilkinson, Howard D. Rees¶, Qing Huai||, Hengming Ke||, Allan I. Levey¶, Lian Li**, and Lih-Shen Chin

From the Departments of Pharmacology, Biochemistry, and ^¶Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322-3090 and the ^||Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7260

Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.

Received for publication, October 7, 2003 , and in revised form, December 5, 2003.

^* This work was supported by grants from the University Research Committee of Emory University and the Emory Collaborative Center (Grant ES012068) for Environmental Research on Parkinson's Disease (to L.-S. C.) and by National Institutes of Health Grants AG021489 and NS047199 and an Emory Center for Neurodegenerative Disease-Merck Scholar Award (to L. L.). 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.

^** To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322-3090. Tel.: 404-727-5987; Fax: 404-727-0365; E-mail: lianli{at}pharm.emory.edu.

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