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J. Biol. Chem., Vol. 283, Issue 29, 20288-20298, July 18, 2008

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-Synuclein Protofibrils Inhibit 26 S Proteasome-mediated Protein Degradation

UNDERSTANDING THE CYTOTOXICITY OF PROTEIN PROTOFIBRILS IN NEURODEGENERATIVE DISEASE PATHOGENESIS^*

Nan-Yan Zhang, Zhiyong Tang, and Chang-Wei Liu¹

From the Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045 and National Center for Nanoscience and Technology, Beijing 10080, China

The impaired ubiquitin-proteasome activity is believed to be one of the leading factors that contribute to Parkinson disease pathogenesis partially by causing -synuclein aggregation. However, the relationship between -synuclein aggregation and the impaired proteasome activity is yet unclear. In this study, we examined the effects of three soluble -synuclein species (monomer, dimer, and protofibrils) on the degradation activity of the 26 S proteasome by reconstitution of proteasomal degradation using highly purified 26 S proteasomes and model substrates. We found that none of the three soluble -synuclein species impaired the three distinct peptidase activities of the 26 S proteasome when using fluorogenic peptides as substrates. In striking contrast, -synuclein protofibrils, but not monomer and dimer, markedly inhibited the ubiquitin-independent proteasomal degradation of unstructured proteins and ubiquitin-dependent degradation of folded proteins when present at 5-fold molar excess to the 26 S proteasome. Together these results indicate that -synuclein protofibrils have a pronounced inhibitory effect on 26 S proteasome-mediated protein degradation. Because -synuclein is a substrate of the proteasome, impaired proteasomal activity could further cause -synuclein accumulation/aggregation, thus creating a vicious cycle and leading to Parkinson disease pathogenesis. Furthermore we found that -synuclein protofibrils bound both the 26 S proteasome and substrates of the 26 S proteasome. Accordingly we propose that the inhibitory effect of -synuclein protofibrils on 26 S proteasomal degradation might result from impairing substrate translocation by binding the proteasome or sequestrating proteasomal substrates by binding the substrates.

Received for publication, December 28, 2007 , and in revised form, May 22, 2008.

^* This work was supported by grants from the American Parkinson Disease Association and Parkinson Disease Foundation (to C.-W. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, P. O. Box 6511, Mail Stop 8101, Aurora, CO 80045. Tel.: 303-724-3208; E-mail: Changwei.liu{at}uchsc.edu.

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