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J. Biol. Chem., Vol. 280, Issue 34, 30009-30017, August 26, 2005

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-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability^*

Qinghua Chen, Jeffrey Thorpe, and Jeffrey N. Keller

From the Sanders-Brown Center on Aging, The Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536

-Synuclein appears to play a role in mediating neurotoxicity in a number of neurodegenerative disorders, collectively referred to as synucleinopathies. Most of these disorders are associated with aging and a probable impairment of the proteasome-proteolytic pathway, although the relationship between aging, proteasome inhibition, and -synuclein toxicity has not been fully elucidated. Recent studies suggest that yeast may provide a useful system for studying the biology and toxicity of -synuclein in mitotic cells, recapitulating many features observed in the various synucleinopathy disorders. Additional studies indicate that the stationary phase model of aging in yeast provides a useful system for understanding the biochemistry and regulation of aging in post-mitotic cells. In the present study we examined the effect of wild type and mutant -synuclein (A30P) on multiple aspects of proteasome homeostasis, protein synthesis, as well as the ability of cells to survive stationary phase aging. These data demonstrate that -synuclein alters proteasome composition, impairs proteasome-mediated protein degradation, impairs protein synthesis, and impairs the ability of cells to withstand stationary phase aging. Interestingly, -synuclein had little effect on intracellular proteasome content or protein ubiquitination, and did not increase the vulnerability of cells to a variety of stressors. Together, these data suggest that yeast may be useful for understanding the ability of -synuclein to impair proteasome-mediated protein degradation, as well as for understanding the basis for age-related -synuclein cytotoxicity.

Received for publication, February 3, 2005 , and in revised form, May 26, 2005.

^* This work was supported National Institutes of Health Grants AG018437 (to J. N. K) and AG005119 (to J. N. K). 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: 205 Sanders-Brown Center on Aging, 800 South Limestone, University of Kentucky, Lexington, KY 40536-0230. Tel.: 859-257-1412 (ext. 333); Fax: 859-323-2866; E-mail: jnkell0{at}pop.uky.edu.

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