Rapamycin alleviates toxicity of different aggregate-prone proteins

被引:530
作者
Berger, Z
Ravikumar, B
Menzies, FM
Oroz, LG
Underwood, BR
Pangalos, MN
Schmitt, I
Wullner, U
Evert, BO
O'Kane, CJ
Rubinsztein, DC
机构
[1] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2XY, England
[2] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England
[3] W Suffolk Hosp, Dept Psychiat, Suffolk Mental Hlth Partnership NHS Trust, Bury St Edmunds IP33 2QZ, Suffolk, England
[4] Univ Klinikum Bonn, D-53105 Bonn, Germany
[5] Wyeth Res, Princeton, NJ 08543 USA
基金
英国惠康基金; 英国医学研究理事会;
关键词
D O I
10.1093/hmg/ddi458
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease (HD) and mutant tau in fronto-temporal dementia/tauopathy. Previously, we showed that rapamycin, an autophagy inducer, enhances mutant huntingtin fragment clearance and attenuated toxicity. Here we show much wider applications for this approach. Rapamycin enhances the autophagic clearance of different proteins with long polyglutamines and a polyalanine-expanded protein, and reduces their toxicity. Rapamycin also reduces toxicity in Drosophila expressing wild-type or mutant forms of tau and these effects can be accounted for by reductions in insoluble tau. Thus, our studies suggest that the scope for rapamycin as a potential therapeutic in aggregate diseases may be much broader than HD or even polyglutamine diseases.
引用
收藏
页码:433 / 442
页数:10
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