![]() If soluble, the substrates associated with chaperones, such as Hsp70, are ubiquitinated by Ub ligases and degraded through the proteasome complex. If such an effort fails, chaperones can facilitate the degradation of terminally misfolded proteins through either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). To prevent the accumulation of disease-causing aggregates, neurons utilize a repertoire of chaperones that recognize misfolded proteins through exposed hydrophobic surfaces and assist their refolding. In fact, many neurodegenerative diseases are considered to be protein misfolding disorders. Failure in PQC is often associated with neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and prion disease. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. 3Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, South Korea.2Technion Integrated Cancer Center, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.1Department of Biomedical Sciences, Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul, South Korea.Aaron Ciechanover 1,2 Yong Tae Kwon 1,3 * ![]()
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