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 (SODI) 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 SODI gene is the greatest breakthrough in ALS research since Charcot's description of the disorder, but the putative toxic gain of function of mutant SODI remains elusive despite intense research. Currently, two dominant theories for the pathogenesis of SODI mutations exist: specific protein cytotoxicity and protein aggregation. Mutant SODI 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 SODI 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 SODI mutations.