Alsin and SOD1(G93A) proteins regulate endosomal reactive oxygen species production by glial cells and proinflammatory pathways responsible for neurotoxicity.

Recent studies have implicated enhanced Nox2-mediated reactive oxygen species by microglia in the pathogenesis of motor neuron death observed in familial amyotrophic lateral sclerosis (ALS). In this context, ALS mutant forms of SOD1 enhance Rac1 activation, leading to increased Nox2-dependent microglial production and neuron cell death in mice. It remains unclear if other genetic mutations that cause ALS also function through similar Nox-dependent pathways to enhance motor neuron death. In the present study, we sought to understand whether alsin, which is mutated in an inherited juvenile form of ALS, functionally converges on Rac1-dependent pathways acted upon by SOD1(G93A) to regulate Nox-dependent duanyu1670 production. Our studies demonstrate that glial cell expression of SOD1(G93A) or wild type alsin induces duanyu1670 production, Rac1 activation, secretion of TNFα, and activation of NFκB, leading to decreased motor neuron survival in co-culture. Interestingly, coexpression of alsin, or shRNA against Nox2, with SOD1(G93A) in glial cells attenuated these proinflammatory indicators and protected motor neurons in co-culture, although shRNAs against Nox1 and Nox4 had little effect. SOD1(G93A) expression dramatically enhanced TNFα-mediated endosomal duanyu1670 in glial cells in a Rac1-dependent manner and alsin overexpression inhibited SOD1(G93A)-induced endosomal duanyu1670 and Rac1 activation. SOD1(G93A) expression enhanced recruitment of alsin to the endomembrane compartment in glial cells, suggesting that these two proteins act to modulate Nox2-dependent endosomal duanyu1670 and proinflammatory signals that modulate NFκB. These studies suggest that glial proinflammatory signals regulated by endosomal duanyu1670 are influenced by two gene products known to cause ALS.

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