TRANSGENIC MICE EXPRESSING AN ALTERED MURINE SUPEROXIDE-DISMUTASE GENE PROVIDE AN ANIMAL-MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis is a progressive neurodegenerative disor der primarily involving motoneurons. A subset of individuals with fami lial autosomal dominant forms of the disease have mutations of the cop per/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free ra dical scavenging. This observation suggests that altered or reduced SO D-1 activity may play a role in the neurodegenerative process. To expl ore this possibility further, we have introduced a mutation into the m ouse SOD-1 gene that corresponds to one of the changes found in the hu man gene in familial amyotrophic lateral sclerosis. Integration and ex pression of this mouse gene in transgenic mice was identified by the p resence of a unique restriction enzyme site in the transgene coding se quence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of moto neurons within the spinal cord, brain stem, and neocortex. These findi ngs indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate norma l levels of total SOD activity in transgenic mouse tissues, results th at indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant ''gain of function'' mutation.