Pathophysiology of neurodegeneration in familial amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. Ten percent of ALS cases are familial, with both autosomal dominant and recessive modes of inheritance reported. Mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the first gene linked with ALS, result in the classical ALS phenotype. To date, 135 mutations have been identified in the SOD-1 gene, accounting for approximately 20% of familial ALS cases. Mutations are widely distributed throughout the gene with preponderance for exon 4 and 5. Although mutations result in a toxic gain of function of the SOD-1 enzyme, which normally functions as a free radical scavenger, the mechanisms underlying motor neuron degeneration have not been clearly elucidated. Evidence is emerging of a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. The clinical effectiveness afforded by anti-glutamatergic agents such as riluzole, suggests that glutamate excitotoxicity contributes to neurodegeneration in ALS, with glutamate excitotoxicity mediated via corticomotoneurons that provide a direct link between the motor cortex and the spinal motor neuron. This review provides an overview of the genetics of ALS, and describes recent advances in the understanding of the pathophysiological mechanisms underlying neurodegeneration.
Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
Steve
S
Vucic
Matthew C
MC
Kiernan
D000690:Amyotrophic Lateral Sclerosis / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D064531:Peripherins; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D064531:Peripherins; C000606290:SOD1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D042461:Vascular Endothelial Growth Factor A; D018698:Glutamic Acid; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D000254:Sodium-Potassium-Exchanging ATPase