title: Role of chaperone-mediated autophagy in degrading Huntington's disease-associated huntingtin protein.
abstract: 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.
authors: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors: Lin
authors: L
authors: Qi
authors: Xing-Ding
authors: XD
authors: Zhang
mesh_terms: D020816:Amino Acid Motifs; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002403:Cathepsins / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D018832:Molecular Chaperones / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*
chemical_list: D050883:HSC70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D002403:Cathepsins
keywords: Huntington's disease (HD); chaperone-mediated autophagy (CMA); chaperones; lysosome-associated membrane protein 2A (LAMP-2A)