The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation
Copyright policy )The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation
Huntington Disease (HD) is caused by an abnormal expansion of polyQ tract in the protein named huntingtin (Htt). HD pathology is featured by accumulation and aggregation of mutant Htt in striatal and cortical neurons. Aberrant Htt degradation is implicated in HD pathogenesis. The aim of this study was to investigate the regulatory role of chaperone-mediated autophagy (CMA) components, heat shock protein cognate 70 (Hsc70) and lysosome-associated protein 2A (LAMP-2A) in degradation of Htt fragment 1-552aa (Htt-552). A cell model of HD was produced by overexpression of Htt-552 with adenovirus. The involvement of CMA components in degradation of Htt-552 was determined with over-expression or silencing of Hsc70 and LAMP-2A. The results confirmed previous reports that both macroautophagy and CMA were involved in degradation of Htt-552. Changing the levels of CMA-related proteins affected the accumulation of Htt-552. The lysosomal binding and luminal transport of Htt-552 was demonstrated by incubation of Htt-552 with isolated lysosomes. Expansion of the polyQ tract in Htt-552 impaired its uptake and degradation by lysosomes. Mutation of putative KFERQ motif in wild-type Htt-552 interfered with interactions between Htt-552 and Hsc70. Endogenous Hsc70 and LAMP-2A interacted with exogenously expressed Htt-552. Modulating the levels of CMA related proteins degraded endogenous full-length Htt. These studies suggest that Hsc70 and LAMP-2A through CMA play a role in the clearance of Htt and suggest a novel strategy to target the degradation of mutant Htt.
- Soochow University China (People's Republic of)
- Harvard University United States
Science, Amino Acid Motifs, Blotting, Western, Gene Expression, 610, Nerve Tissue Proteins, PC12 Cells, Neurological Signaling, Lysosomal-Associated Membrane Protein 2, Molecular Cell Biology, 616, Genetics, Autophagy, Signaling in Cellular Processes, Animals, Humans, Amino Acid Sequence, Biology, Huntingtin Protein, Q, R, HSC70 Heat-Shock Proteins, Neurodegenerative Diseases, Signaling in Selected Disciplines, Lysosomal Membrane Proteins, Cellular Structures, Peptide Fragments, Subcellular Organelles, Neurology, Microscopy, Fluorescence, Mutation, Proteolysis, Medicine, Lysosomes, Signal Transduction, Research Article, HeLa Cells, Molecular Chaperones, Protein Binding
Science, Amino Acid Motifs, Blotting, Western, Gene Expression, 610, Nerve Tissue Proteins, PC12 Cells, Neurological Signaling, Lysosomal-Associated Membrane Protein 2, Molecular Cell Biology, 616, Genetics, Autophagy, Signaling in Cellular Processes, Animals, Humans, Amino Acid Sequence, Biology, Huntingtin Protein, Q, R, HSC70 Heat-Shock Proteins, Neurodegenerative Diseases, Signaling in Selected Disciplines, Lysosomal Membrane Proteins, Cellular Structures, Peptide Fragments, Subcellular Organelles, Neurology, Microscopy, Fluorescence, Mutation, Proteolysis, Medicine, Lysosomes, Signal Transduction, Research Article, HeLa Cells, Molecular Chaperones, Protein Binding
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