title: Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.
abstract: Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
authors.affiliation: 1] Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea [2] Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018620:PrPSc Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex