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J. Biol. Chem., Vol. 283, Issue 44, 30289-30299, October 31, 2008

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Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease^*

Jeong-Sun Ju, Sara E. Miller, Phyllis I. Hanson, and Conrad C. Weihl¹

From the Departments of Neurology and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Mutations in p97/VCP cause the multisystem disease inclusion body myopathy, Paget disease of the bone and frontotemporal dementia (IBMPFD). p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and has been implicated in multiple cellular processes. One pathologic feature in IBMPFD is ubiquitinated inclusions, suggesting that mutations in p97/VCP may affect protein degradation. The present study shows that IBMPFD mutant expression increases ubiquitinated proteins and susceptibility to proteasome inhibition. Co-expression of an aggregate prone protein such as expanded polyglutamine in IBMPFD mutant cells results in an increase in aggregated protein that localizes to small inclusions instead of a single perinuclear aggresome. These small inclusions fail to co-localize with autophagic machinery. IBMPFD mutants avidly bind to these small inclusions and may not allow them to traffic to an aggresome. This is rescued by HDAC6, a p97/VCP-binding protein that facilitates the autophagic degradation of protein aggregates. Expression of HDAC6 improves aggresome formation and protects IBMPFD mutant cells from polyglutamine-induced cell death. Our study emphasizes the importance of protein aggregate trafficking to inclusion bodies in degenerative diseases and the therapeutic benefit of inclusion body formation.

Received for publication, July 18, 2008 , and in revised form, August 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant K08 AG026271 (to C. C. W.). This work was also supported by National Institutes of Health Neuroscience Blueprint Core Grant P30 NS057105 to Washington University. 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: Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-6981; Fax: 314-747-3752; E-mail: weihlc{at}neuro.wustl.edu.

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