Human Molecular Genetics Advance Access published online on April 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl110
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1 Departments of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, 48109
* To whom correspondence should be addressed. The molecular chaperone hsp90 has emerged as an important therapeutic target in cancer and neurodegenerative diseases, including the polyglutamine expansion disorders, because of its ability to regulate the activity, turnover and trafficking of many proteins. For neurodegenerative disorders associated with protein aggregation the rationale has been that inhibition of hsp90 by geldanamycin and related compounds activates heat shock factor 1 (HSF1) to induce the production of the chaperones hsp70 and hsp40, which promote disaggregation and protein degradation. However, we show here that geldanamycin blocks the development of aggregates of the expanded glutamine androgen receptor (AR112Q) of Kennedy disease in Hsf1-/- mouse embryonic fibroblasts (MEFs) where these chaperones are not induced. Geldanamycin is additionally known to inhibit hsp90-dependent protein trafficking and to promote proteasomal degradation of client proteins. Overexpression of the hsp90 cochaperone p23 also promotes AR112Q degradation, and inhibits both AR trafficking and AR112Q aggregation without altering levels of hsp70 or hsp40. The hsp90-dependent trafficking mechanism has been defined, and we show that key immunophilin components of the trafficking machinery are present in polyglutamine aggregates in cell and mouse models of Kennedy disease. Our results indicate that inhibition of the hsp90-dependent trafficking mechanism prevents aggregation of the expanded glutamine androgen receptor, thereby opening a variety of novel therapeutic approaches to these neurodegenerative disorders.
Received March 3, 2006
Revised April 17, 2006
Accepted April 17, 2006
Article
Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction
Monzy Thomas 1,
Jennifer M. Harrell 2,
Yoshihiro Morishima 2,
Hwei-Ming Peng 2,
William B. Pratt 2,
and
Andrew P. Lieberman 3 *
2 Departments of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan, 48109
3 Departments of Pathology, The University of Michigan Medical School, 1301 Catherine, 4233 Medical Science 1, Ann Arbor, Michigan, 48109
Andrew P. Lieberman, E-mail: liebermn{at}umich.edu
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