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J. Biol. Chem., Vol. 280, Issue 9, 7562-7569, March 4, 2005

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-Synuclein Reduces Proteasomal Inhibition by -Synuclein but Not -Synuclein^*

Heather Snyder, Kwame Mensah, Cindy Hsu¶, Makoto Hashimoto||, Irina G. Surgucheva**, Barry Festoff**, Andrei Surguchov**, Eliazer Masliah||, Andreas Matouschek, and Benjamin Wolozin¶

From the Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, the Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208, the ^¶Department of Pharmacology, Boston University School of Medicine, Boston, Massachussetts 02118, the ^||Department of Neuroscience, University of California at San Diego, La Jolla, California 92093, the ^**Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, Missouri 64128, and the Department of Neurology, University of Kansas School of Medicine, Kansas City, Kansas 66160

The accumulation of aggregated -synuclein is thought to contribute to the pathogenesis of Parkinson's disease. Recent studies indicate that aggregated -synuclein binds to S6', a component of the 19 S subunit in the 26 S proteasome and inhibits 26 S proteasomal degradation, both ubiquitin-independent and ubiquitin-dependent. The IC₅₀ of aggregated -synuclein for inhibition of the 26 S ubiquitin-independent proteasomal activity is 1nM. -Synuclein has two close homologues, termed -synuclein and -synuclein. In the present study we compared the effects of the three synuclein homologues on proteasomal activity. The proteasome exists as a 26 S and a 20 S species, with the 26 S proteasome containing the 20 S core and 19 S cap. Monomeric - and -synucleins inhibited the 20 S and 26 S proteasomal activities only weakly, but monomeric -synuclein strongly inhibited ubiquitin-independent proteolysis. The IC₅₀ of monomeric -synuclein for the 20 S proteolysis was 400 nM. In monomeric form, none of the three synuclein proteins inhibited 26 S ubiquitin-dependent proteasomal activity. Although -synuclein had no direct effect on proteasomal activity, co-incubating monomeric -synuclein with aggregated -synuclein antagonized the inhibition of the 26 S ubiquitin-independent proteasome by aggregated -synuclein when added before the aggregated -synuclein. Co-incubating -synuclein with -synuclein had no effect on the inhibition of the 20 S proteasome by monomeric -synuclein. Immunoprecipitation and pull-down experiments suggested that antagonism by -synuclein resulted from binding to -synuclein rather than binding to S6'. Pull-down experiments demonstrated that recombinant monomeric -synuclein does not interact with the proteasomal subunit S6', unlike -synuclein, but -synuclein does bind -synuclein and competes with S6' for binding to -synuclein. Based on these data, we hypothesize that the - and -synucleins regulate proteasomal function and that -synuclein acts as a negative regulator of -synuclein.

Received for publication, November 15, 2004

^* This work was supported by NINDS, National Institutes of Health Grant NS41786 (to B. W.) and United States Army Medical Research Command Grant DAMD17-01-1-0781) (to B. W.). 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, Boston University School of Medicine, 715 Albany St., R614, Boston, MA 02118-2526. Tel.: 617-414-2652; Fax: 617-414-2651; E-mail: bwolozin{at}bu.edu.

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