生物谷报道:本期Nature medicine报道了17-AAG,17-allylamino-17-demethoxygeldanamycin作为细胞内HSP90的抑制剂,可以减轻运动 神经元性疾病。
HSP90是细胞内冗余的一类伴侣蛋白,与Hsp70, Hop (Hsp70 and Hsp90 organizing protein), Cdc37, Hsp40 and p23等结合组成伴侣蛋白复合体,目前HSP90已作为癌症,一些退行性病的治疗靶点。
而17-AAG是新近发现的低毒性,高选择性抑制一些癌蛋白,用于癌症的治疗,而本作者发现也可以用于神经退行性疾病的治疗。
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.