17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration.
Nat Med
; 11(10): 1088-95, 2005 Oct.
Article
en En
| MEDLINE
| ID: mdl-16155577
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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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Atrofia Muscular Espinal
/
Rifabutina
/
Proteínas HSP90 de Choque Térmico
/
Neuronas Motoras
Límite:
Animals
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Estados Unidos