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Expression of N19S‐SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induceslow‐grade motoneuronal toxicity

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease. It has been generally accepted that the proapoptotic property of the familial ALS (FALS)‐linked mutant SOD1 genes plays an important role in the pathogenesis of some FALS cases. We found here that expression of N19S‐SOD1, a novel SOD1 mutant originally found in a sporadic ALS patient, induces lower grade death in NSC34 cells than FALS‐linked mutant SOD1. In agreement, intracytoplasmic aggregate formation and SOD1 polymerization are less prominently induced by ectopic expression of N19S‐SOD1 than FALS‐linked mutant SOD1. We further found that additional cell stresses, such as inhibition of proteasomal activity or up‐regulation of intracellular oxidative stress, enhance N19S‐SOD1‐induced aggregate formation and polymerization of N19S‐SOD1. Such analysis of the intracellular polymerization and the ubiquitination of N19S‐SOD1 have further suggested that it is recognized as a misfolded protein, like FALS‐linked mutant SOD1, whereas wild‐type SOD1 is not. Altogether, it is speculated that the N19S mutation of SOD1 in cooperation with associated cell stresses contributes to the onset of ALS as a risk factor. © 2005 Wiley‐Liss, Inc.