Role of chaperone-mediated autophagy in degrading Huntington's disease-associated huntingtin protein |
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基金项目: | This work was supported by grants from the National Natural Science Foundation of China (Nos. 81201861 and 81272476), the Postdoctoral Science Foundation of China (2011M500949), and the Postdoctoral Science Foundation of Jiangsu Province (1102139C). |
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摘 要: | Mutant N-terminal huntingtin (Htt) protein resulting from Huntington's disease (HD) with expanded polyglutamine accumulates and forms aggregates in vulnerable neurons. Both ubiquitin proteasomai and autophagic pathways con- tribute to the degradation of mutant Htt. Here, we focus on the involvement of chaperone-mediated autophagy (CMA), a selective form of autophagy in the clearance of Htt. Selective catabolism in CMA is conferred by the presence of a KFERQ-Iike targeting motif in the substrates, by which molecular chaperones recognize the hydrophobic surfaces of the misfolded substrates, and transfer them to the lysosomal membrane protein type-2A, LAMP-2A. The substrates are taken into the lysosomes through LAMP-2A and are rapidly degraded by the lysosomal enzymes. Taken together, we summarize the recent evidence to elucidate that Htt is also a potential substrate of CMA. We propose that the manipulation of CMA could be a therapeutic strat- egy for HD.
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关 键 词: | 分子伴侣 膜蛋白 酶降解 自噬 介导 CMA Htt 溶酶体 |
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