生物谷報道：本期Nature medicine報道了17-AAG，17-allylamino-17-demethoxygeldanamycin作為細胞內(nèi)HSP90的抑制劑,，可以減輕運動 神經(jīng)元性疾病,。
HSP90是細胞內(nèi)冗余的一類伴侶蛋白，與Hsp70, Hop (Hsp70 and Hsp90 organizing protein), Cdc37, Hsp40 and p23等結(jié)合組成伴侶蛋白復合體,，目前HSP90已作為癌癥,，一些退行性病的治療靶點。
而17-AAG是新近發(fā)現(xiàn)的低毒性,，高選擇性抑制一些癌蛋白,，用于癌癥的治療,，而本作者發(fā)現(xiàn)也可以用于神經(jīng)退行性疾病的治療。
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.
