Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction

Human Molecular Genetics
Monzy ThomasAndrew P Lieberman

Abstract

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 that 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 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 it is shown that key immunophilin (IMM) components of the trafficking m...Continue Reading

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