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J. Biol. Chem., Vol. 279, Issue 18, 18614-18622, April 30, 2004
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¶**
From the
Center for Neurologic Diseases, Brigham and Women's Hospital and ||Department of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115 and ¶Institute for Human Genetics, University Clinic Charité, D-13353 Berlin, Germany
Loss-of-function mutations in parkin are the predominant cause of familial Parkinson's disease. We previously reported that parkin-/- mice exhibit nigrostriatal deficits in the absence of nigral degeneration. Parkin has been shown to function as an E3 ubiquitin ligase. Loss of parkin function, therefore, has been hypothesized to cause nigral degeneration via an aberrant accumulation of its substrates. Here we employed a proteomic approach to determine whether loss of parkin function results in alterations in abundance and/or modification of proteins in the ventral midbrain of parkin-/- mice. Two-dimensional gel electrophoresis followed by mass spectrometry revealed decreased abundance of a number of proteins involved in mitochondrial function or oxidative stress. Consistent with reductions in several subunits of complexes I and IV, functional assays showed reductions in respiratory capacity of striatal mitochondria isolated from parkin-/- mice. Electron microscopic analysis revealed no gross morphological abnormalities in striatal mitochondria of parkin-/- mice. In addition, parkin-/- mice showed a delayed rate of weight gain, suggesting broader metabolic abnormalities. Accompanying these deficits in mitochondrial function, parkin-/- mice also exhibited decreased levels of proteins involved in protection from oxidative stress. Consistent with these findings, parkin-/- mice showed decreased serum antioxidant capacity and increased protein and lipid peroxidation. The combination of proteomic, genetic, and physiological analyses reveal an essential role for parkin in the regulation of mitochondrial function and provide the first direct evidence of mitochondrial dysfunction and oxidative damage in the absence of nigral degeneration in a genetic mouse model of Parkinson's disease.
Received for publication, February 2, 2004 , and in revised form, February 19, 2004.
* This work was supported by a Harvard Center for Neurodegeneration and Repair Translational Research Fellowship (to J. J. P.), by Bundesministerium fuer Bildung und Forschung (to D. S. and J. K.), and by grants from NINDS, National Institutes of Health (to J. S.). 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.
These authors contributed equally to this work.
** To whom correspondence should be addressed: Center for Neurologic Diseases, Harvard Medical School, New Research Bldg. 636E, 77 Avenue Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5561; Fax: 617-525-5522; E-mail: jshen{at}rics.bwh.harvard.edu.
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