title: The complex molecular biology of amyotrophic lateral sclerosis (ALS).
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that causes selective death of motor neurons followed by paralysis and death. A subset of ALS cases is caused by mutations in the gene for Cu, Zn superoxide dismutase (SOD1), which impart a toxic gain of function to this antioxidant enzyme. This neurotoxic property is widely believed to stem from an increased propensity to misfold and aggregate caused by decreased stability of the native homodimer or a tendency to lose stabilizing posttranslational modifications. Study of the molecular mechanisms of SOD1-related ALS has revealed a complex array of interconnected pathological processes, including glutamate excitotoxicity, dysregulation of neurotrophic factors and axon guidance proteins, axonal transport defects, mitochondrial dysfunction, deficient protein quality control, and aberrant RNA processing. Many of these pathologies are directly exacerbated by misfolded and aggregated SOD1 and/or cytosolic calcium overload, suggesting the primacy of these events in disease etiology and their potential as targets for therapeutic intervention.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Redler
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D009414:Nerve Growth Factors / Q000378:metabolism; D017510:Protein Folding; D055503:Protein Multimerization; D012323:RNA Processing, Post-Transcriptional; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D057170:Translational Research, Biomedical
chemical_list: D009414:Nerve Growth Factors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1