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Article
Nature Medicine 11, 1088 - 1095 (2005)
Published online: 11 September 2005 | doi:10.1038/nm1298
17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration
Masahiro Waza1,2, Hiroaki Adachi1,2, Masahisa Katsuno1, Makoto Minamiyama1, Chen Sang1, Fumiaki Tanaka1, Akira Inukai1, Manabu Doyu1 & Gen Sobue1
Abstract
Heat-shock protein 90 (Hsp90) functions as part of a multichaperone complex that folds, activates and assembles its client proteins. Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins. We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR. Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR. The mutant AR showed a higher affinity for Hsp90-p23 and preferentially formed an Hsp90 chaperone complex as compared to wild-type AR; mutant AR was preferentially degraded in the presence of 17-AAG in both cells and transgenic mice as compared to wild-type AR. 17-AAG also mildly induced Hsp70 and Hsp40. 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases.
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