title: Protein folding alterations in amyotrophic lateral sclerosis.
abstract: Protein misfolding leads to the formation of aggregated proteins and protein inclusions, which are associated with synaptic loss and neuronal death in neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord. Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72. Chaperone proteins, including heat shock proteins (Hsp׳s) and the protein disulphide isomerase (PDI) family, assist in protein folding and therefore can prevent protein misfolding, and have been implicated as being protective in ALS. In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention. This article is part of a Special Issue entitled SI:ER stress.
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, NSW, 2109 Australia.
authors.forename: Sonam
authors.initials: S
authors.lastname: Parakh
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, NSW, 2109 Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia. Electronic address: julie.atkin@mq.edu.au.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D000073885:C9orf72 Protein / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation / Q000235:genetics; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D018832:Molecular Chaperones; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; C9ORF72; Disulphide bonds; ER stress; FUS; Protein disulphide isomerase (PDI); Protein misfolding; Superoxide dismutase 1 (SOD1); TDP-43