MUTANT SUPEROXIDE DISMUTASE-1-LINKED FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS - MOLECULAR MECHANISMS OF NEURONAL DEATH AND PROTECTION

Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause similar to 20% of cases of familial amyotrophic lateral sclerosis (FALS). We inv estigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of in fection with replication-deficient recombinant adenoviruses. Expressio n of two FALS-related mutant SODs (A4V and V148G) caused death of diff erentiated PC12 cells, superior cervical ganglion neurons, and hippoca mpal pyramidal neurons. Cell death included many features typical of a poptosis. Death could be prevented by copper (Cu2+) chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. Mutant SOD-express ing PC12 cells had higher rates of superoxide (O-2(-)) production unde r a variety of conditions. The results support the hypothesis that mut ant SOD induced-neurodegeneration is associated with disturbances of n euronal free radical homeostasis.