Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.

This review highlights recent epidemiologic, clinical-genetic, and neurochemical advances in our understanding of sporadic amyotrophic lateral sclerosis (ALS) and their relationships to familial ALS caused by superoxide dismutase (SOD1) gene mutations. It is of fundamental importance to recognize that ALS is a biologically heterogeneous syndrome in which genetics, environment, and aging are inter-related. The discovery of mutations in the SOD1 gene is the greatest breakthrough in ALS research since Charcot's description of the disorder, but the putative toxic gain of function of mutant SOD1 remains elusive despite intense research. Currently, two dominant theories for the pathogenesis of SOD1 mutations exist: specific protein cytotoxicity and protein aggregation. Mutant SOD1 interacts specifically with neurofilament-light chain mRNA and the dynein/dynactin complex, suggesting that cytoskeletal defects and axonal transport are key players. In addition, mutant SOD1 protein has increased propensity to form aggregate-prone monomers, and the degree of instability correlates inversely with length of survival; therefore, increased propensity to aggregate may be the unifying common denominator for the 119 diverse SOD1 mutations.