期刊
CELL DEATH AND DIFFERENTIATION
卷 16, 期 1, 页码 46-56出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2008.110
关键词
autophagy; Huntington's disease; rapamycin
资金
- MRC
- Wellcome Trust
- EU Framework VI (EUROSCA)
- National Institute for Health Research Biomedical Research Centre at Addenbrooke's Hospital
- MRC [G0600194] Funding Source: UKRI
- Medical Research Council [G0600194] Funding Source: researchfish
The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin ( mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca2+ -calpain-G(s alpha) and cAMP-Epac-PLC-epsilon-IP3 signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes ( like mild translation suppression). Also, the mTOR-independent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据