title: Failure of protein quality control in amyotrophic lateral sclerosis.
abstract: The protein chaperoning and ubiquitin-proteasome systems perform many homeostatic functions within cells involving protein folding, transport and degradation. Of paramount importance is ridding cells of mutant or post-translationally modified proteins that otherwise tend to aggregate into insoluble complexes and form inclusions. Such inclusions are characteristic of many neurodegenerative diseases and implicate protein misfolding and aggregation as common aspects of pathogenesis. In the most common familial form of ALS, mutations in SOD1 promote misfolding of the protein and target it for degradation by proteasomes. Although proteasomes can degrade the mutant proteins efficiently, altered solubility and aggregation of mutant SOD1 are features of the disease and occur most prominently in the most vulnerable cells and tissues. Indeed, lumbar spinal cord of mutant SOD1 transgenic mice show early reduction in their capacity for protein chaperoning and proteasome-mediated hydrolysis of substrates, and motor neurons are particularly vulnerable to aggregation of mutant SOD1. A high threshold for upregulating key pathways in response to the stress of added substrate load may contribute to this vulnerability. The broad spectrum neuroprotective capability and efficacy of some chaperone-based therapies in preclinical models makes these pathways attractive as targets for therapy in ALS, as well as other neurodegenerative diseases. A better understanding of the mechanisms governing the regulation of protein chaperones and UPS components would facilitate development of treatments that upregulate these pathways in a coordinated manner in neural tissue without long term toxicity.
authors.affiliation: Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill University, 3801 University St., Montreal QC, Canada H3A 2B4.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008159:Lumbar Vertebrae / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000502:physiology*; D017510:Protein Folding; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin / Q000737:chemistry / Q000502:physiology*
chemical_list: D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D025801:Ubiquitin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex