Our results indicate that hsp90 inhibitors prevent aggregation of the expanded glutamine AR independent of a stress response, and instead, act by inhibiting hsp90 mediated retrograde trafficking. We sought to determine whether stress protein induction was required for this effect. Recent studies showed that the hsp90 inhibitor 17-AAG prevents aggregation of the expanded glutamine AR and ameliorates motor neuron degeneration in a transgenic mouse model of the Kennedy disease ( 20). In Kennedy disease, an expanded glutamine tract near the amino terminus of the androgen receptor (AR) leads to hormone-dependent protein misfolding, aggregate formation in the cell cytoplasm and nucleus ( 18), and the predominant loss of lower motor neurons in the brainstem and spinal cord of the affected males ( 19). Like Huntington disease, Kennedy disease, or spinal and bulbar muscular atrophy, is one of nine neurodegenerative disorders that results from the expansion of a CAG/glutamine tract in the coding region of otherwise unrelated genes ( 17). If inhibition of hsp90 is to become a therapeutic approach for the treatment of protein aggregation neurodegenerative disorders, it is important to define the mechanistic basis for this effect. However, this hypothesis has not been critically tested. Because geldanamycin induces heat shock proteins, and overexpression of hsp70 and hsp40 inhibits aggregation of expanded polyglutamine proteins and α-synuclein ( 10– 16), it has been proposed that geldanamycin alleviates the phenotype and the accumulation of misfolded proteins in models of Huntington and Parkinson diseases by inducing a stress response ( 5– 7, 16). hsp90 complex, and treatment of cells with geldanamycin induces an HSF1-dependent heat shock response ( 5– 9).The chaperone machinery is a negative regulator of heat shock factor 1 (HSF1) ( 8) by maintaining it in an inactive apo-HSF1 The neuroprotective effect of geldanamycin is thought to be based on a different outcome of hsp90 inhibition. hsp90 heterocomplexes is also part of the cellular defense against unfolded proteins ( 4), and geldanamycin has been reported to inhibit protein aggregation in models of Huntington ( 5, 6) and Parkinson diseases ( 7).The hsp90/hsp70-based chaperone machinery ( 1) that forms signaling protein Specific inhibition of hsp90 by drugs like geldanamycin and radicicol leads to the proteasomal degradation of hsp90-associated oncoproteins ( 2), and this is the basis for clinical trials of the hsp90 inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in cancer patients ( 3). Hsp90 is an abundant molecular chaperone that controls the activity, turnover and trafficking of many proteins, in particular the mediators of signal transduction ( 1), and as such plays a critical role at regulatory points implicated in the pathogenesis of cancer and neurodegenerative diseases. 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. The hsp90-dependent trafficking mechanism has been defined, and it is shown that key immunophilin (IMM) components of the trafficking machinery are present in polyglutamine aggregates in cell and mouse models of Kennedy disease. 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. Geldanamycin is additionally known to inhibit hsp90-dependent protein trafficking and to promote proteasomal degradation of client proteins. 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. 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. 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.
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