Transgenic animal models of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) occurs in both sporadic and familial forms, which have very similar clinical presentation and course. Approximately 20% of the familial cases of ALS are caused by mutation of the SODI gene encoding Cu, Zn superoxide dismutase (SOD). Over 30 different SODI gene mutations have been found in patients. Most are missense mutations that cause the substitution of one amino acid for another. The failure to find deletions in familial ALS suggests that the mutant protein is required for pathogenesis. Studies in transgenic mice indicate that familial ALS is caused by gain-of-function mutations in the SODI gene. These enhance formation of free radicals by the mutant enzyme. When expressed at high levels in transgenic mice, mutant human Cu,Zn SOD causes a clinical disease that resembles human ALS. Selective degeneration of motor neurones in the spinal cord and brainstem is accompanied by progressive motor impairment. Pathogenesis in the transgenic model of familial ALS is a sequential, two-step process in which damage mediated by free radicals accumulates to a threshold that triggers catastrophic motor neurone loss through glutamate-mediated, excitotoxic mechanisms. Evidence in support of this hypothesis comes from therapeutic studies with antioxidants and inhibitors of glutamatergic neurotransmission.