Current hypotheses for the underlying biology of amyotrophic lateral sclerosis.
The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.
Rothstein
Jeffrey D
JD
Department of Neurology and Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287, USA. jrothstein@jhmi.edu
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D009457:Neuroglia / Q000473:pathology; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D012313:RNA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases