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J. Biol. Chem., Vol. 283, Issue 26, 17962-17968, June 27, 2008

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CHIP Targets Toxic -Synuclein Oligomers for Degradation^*

From the Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129

-Synuclein (Syn) can self-associate, forming oligomers, fibrils, and Lewy bodies, the pathological hallmark of Parkinson disease. Current dogma suggests that oligomeric Syn intermediates may represent the most toxic Syn species. Here, we studied the effect of a potent molecular chaperone, CHIP (carboxyl terminus of Hsp70-interacting protein), on Syn oligomerization using a novel bimolecular fluorescence complementation assay. CHIP is a multidomain chaperone, utilizing both a tetratricopeptide/Hsp70 binding domain and a U-box/ubiquitin ligase domain to differentially impact the fate of misfolded proteins. In the current study, we found that co-expression of CHIP selectively reduced Syn oligomerization and toxicity in a tetratricopeptide domain-dependent, U-box-independent manner by specifically degrading toxic Syn oligomers. We conclude that CHIP preferentially recognizes and mediates degradation of toxic, oligomeric forms of Syn. Further elucidation of the mechanisms of CHIP-induced degradation of oligomeric Syn may contribute to the successful development of drug therapies that target oligomeric Syn by mimicking or enhancing the powerful effects of CHIP.

Received for publication, March 24, 2008

^* 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.

¹ To whom correspondence should be addressed: Alzheimer Disease Research Unit, Dept. of Neurology, Massachusetts General Hospital, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-1263; Fax: 617-724-1480; E-mail: pmclean{at}partners.org.

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