Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
Acta Biochim Biophys Sin (Shanghai). 2014 Feb;46(2):83-91. doi: 10.1093/abbs/gmt133. Epub 2013 Dec 8.
Mutant N-terminal huntingtin (Htt) protein resulting from Huntington's disease (HD) with expanded polyglutamine accumulates and forms aggregates in vulnerable neurons. Both ubiquitin proteasomal and autophagic pathways contribute 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-like 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 strategy for HD.
突变的 N 端亨廷顿蛋白（Htt）是由亨廷顿病（HD）引起的，其具有扩展的多聚谷氨酰胺并在易受影响的神经元中积聚形成聚集体。泛素蛋白酶体和自噬途径都有助于突变 Htt 的降解。在这里，我们重点关注伴侣介导的自噬（CMA）的参与，这是自噬清除 Htt 的一种选择性形式。CMA 中的选择性分解代谢是由底物中存在 KFERQ 样靶向基序赋予的，分子伴侣通过该靶向基序识别错误折叠底物的疏水性表面，并将其转移到溶酶体膜蛋白 2A（LAMP-2A）上。底物通过 LAMP-2A 进入溶酶体，并被溶酶体酶迅速降解。综上所述，我们总结了最近的证据，以阐明 Htt 也是 CMA 的潜在底物。我们提出，操纵 CMA 可能是治疗 HD 的一种策略。
