MUTANT CUZN SUPEROXIDE-DISMUTASE IN MOTOR-NEURON DISEASE

CuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enz ymes that defend the cell. against damage by oxygen free radicals. Mut ations of the SOD1 gene encoding CuZn SOD are found in patients with f amilial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cort ex, brainstem and spinal cord. The disease can be reproduced in transg enic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutatio n converts a protective, antioxidant enzyme into a destructive, prooxi dant form that catalyses free radical damage to which motor neurons ar e selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper ch elation therapy, dietary antioxidants, and coexpression of bcl-2) dela ys disease onset but does not extend disease duration. In contrast, in hibition of glutamatergic or apoptotic mechanisms (riluzole, gabapenti n, and coexpression of an inhibitor of caspase-1) has no effect on dis ease onset but extends survival by increasing the duration of symptoma tic disease. Thus, neuroprotective agents differentially target the pr ocesses underlying disease initiation and propagation.