Amyotrophic lateral sclerosis: lessons from mouse and human genetics

Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly fatal, adult-onset degenerative disorder of motor neurons. It is now clear that cases arise as dominant traits because of mutations in a gene encoding the cytosolic, Cu/Zn superoxide dismutase (SOD1). Several lines of evidence favor the view that the mutations con fer one or more no urotoxic properties on the mutant protein. The mechanisms whereby mSOD I is cytotoxic are unknown. However, several observations are relevant, (1) The mutant SOD1 proteins are con formationally less stable than the wild-type protein, with reduced affinity for zinc and a more readily reducible copper ion, This may lead directly (via metal toxicity) or indirectly (via altered binding properties of the mutant SODI protein or protein aggregation) to neurotoxicity. (2) Many of the mutants hake an enhanced capacity to promote nitrotyrosine formation or act as oxidases. (3) In most cases of human and murine ALS, there is increased oxidative pathology, (4) In ALS mice, axonal transport and mitochondrial function are impaired. (5)The importance of axonal transport, and the neuronal cytoskeleton more generally is emphasized by the observation that rare cases of ALS are associated with mutations in the neurofilament heady subunit gene. (6) Both in mSOD1-mediated and sporadic ALS. data implicate glutamate excitotoxicity as a disease-accelerating factor. Taken together, these consideration,, suggest a model in which multiple events act in concert to triggerdeath in motor neurons. A downstrearn consequence is late-stage activation of cell death genes. This model has significant implications for the development of therapeutic strategies for ALS and related disorders. (C) 2001 Published by Assocation lot Research in Nervous and Mental Disease.