FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis is sporadic in ninety percent of cases a nd familial (FALS) in ten percent. Both forms of FALS whether transmit ted as an autosomal dominant (DFALS) or as an autosomal recessive (RFA LS) trait is genetically heterogeneous. The locus for one form of RFAL S maps to chromosome 2q33. Fifteen percent of DFALS families have muta tions in the gene for Cu, Zn superoxide dismutase (SOD1) gene which is coded on chromosome 21. These mutations result in decreased SOD1 acti vity and shortened half-life of the protein in most instances. Transge nic mice overexpressing mutated SOD1 protein develop an ALS-like disea se which suggests that the degeneration of motor neurons in DFALS is c aused by the gain of a novel toxic function by mutated SOD1 rather tha n by the decrease of SOD1 activity. Possible mechanisms of the novel n eurotoxic function of mutated SOD1 are discussed.