TRANSGENIC ANIMAL-MODELS OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis (ALS) occurs in both sporadic and famili al forms, which have very similar clinical presentation and course. Ap proximately 20% of the familial cases of ALS are caused by mutation of the SOD1 gene encoding Cu,Zn superoxide dismutase (SOD). Over 30 diff erent SOD1 gene mutations have been found in patients. Most are missen se mutations that cause the substitution of one amino acid for another . The failure to find deletions in familial ALS suggests that the muta nt protein is required for pathogenesis. Studies in transgenic mice in dicate that familial ALS is caused by gain-of-function mutations in th e SOD1 gene. These enhance formation of free radicals by the mutant en zyme, When expressed at high levels in transgenic mice, mutant human C u,Zn SOD causes a clinical disease that resembles human ALS. Selective degeneration of motor neurones in the spinal cord and brainstem is ac companied by progressive motor impairment. Pathogenesis in the transge nic model of familial ALS is a sequential, two-step process in which d amage mediated by free radicals accumulates to a threshold that trigge rs catastrophic motor neurone loss through glutamate-mediated, excitot oxic mechanisms. Evidence in support of this hypothesis comes from the rapeutic studies with antioxidants and inhibitors of glutamatergic neu rotransmission.