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Proteomic Identification of a Stress Protein, Mortalin/mthsp70/GRP75: Relevance To Parkinson Disease*S

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Functional impairment of mitochondria and proteasomes and increased oxidative damage comprise the main pathological phenotypes of Parkinson disease (PD). Using an unbiased quantitative proteomic approach, we compared nigral mitochondrial proteins of PD patients with those from age-matched controls. 119 of 842 identified proteins displayed significant differences in their relative abundance (increase/decrease) between the two groups. We confirmed that one of these, mortalin (mthsp70/GRP75, a mitochondrial stress protein), is substantially decreased in PD brains as well as in a cellular model of PD. In addition, nine candidate mortalin-binding partners were identified as potential mediators of PD pathology. Manipulations of mortalin level in dopaminergic neurons resulted in significant changes in sensitivity to PD phenotypes via pathways involving mitochondrial and proteasomal function as well as oxidative stress.

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Published, MCP Papers in Press, March 24, 2006, DOI 10.1074/mcp.M500382-MCP200

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This work was supported by the National Institutes of Health Grants ES012703 and AG025327 (to J. Z.). 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.

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The on-line version of this article (available at http://www.mcponline.org) contains supplemental material.