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Alsin and SOD1(G93A) proteins regulate endosomal reactive oxygen species production by glial cells and proinflammatory pathways responsible for neurotoxicity
Journal article   Open access   Peer reviewed

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

Qiang Li, Netanya Y Spencer, Nicholas J Pantazis and John F Engelhardt
The Journal of biological chemistry, Vol.286(46), pp.40151-40162
11/18/2011
DOI: 10.1074/jbc.M111.279711
PMCID: PMC3220533
PMID: 21937428
url
https://doi.org/10.1074/jbc.M111.279711View
Published (Version of record) Open Access

Abstract

Recent studies have implicated enhanced Nox2-mediated reactive oxygen species (ROS) 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 ROS 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 ROS-mediate 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 ROS production. Our studies demonstrate that glial cell expression of SOD1(G93A) or wild type alsin induces ROS 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 ROS in glial cells in a Rac1-dependent manner and alsin overexpression inhibited SOD1(G93A)-induced endosomal ROS 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 ROS and proinflammatory signals that modulate NFκB. These studies suggest that glial proinflammatory signals regulated by endosomal ROS are influenced by two gene products known to cause ALS.
 Tumor Necrosis Factor-alpha - metabolism Inflammation - pathology Superoxide Dismutase - genetics Reactive Oxygen Species - metabolism Membrane Glycoproteins - metabolism Neuroglia - pathology Humans Tumor Necrosis Factor-alpha - genetics NADPH Oxidases - metabolism rac GTP-Binding Proteins - metabolism Inflammation - metabolism Guanine Nucleotide Exchange Factors - metabolism rac GTP-Binding Proteins - genetics NADPH Oxidases - genetics Amyotrophic Lateral Sclerosis - enzymology Neuropeptides - genetics NADH, NADPH Oxidoreductases - metabolism Superoxide Dismutase - metabolism Cell Line NADH, NADPH Oxidoreductases - genetics Guanine Nucleotide Exchange Factors - genetics Endosomes - genetics Amyotrophic Lateral Sclerosis - genetics Neuroglia - enzymology Neuropeptides - metabolism Signal Transduction - genetics NADPH Oxidase 4 NADPH Oxidase 2 Nerve Tissue Proteins - genetics NADPH Oxidase 1 Membrane Glycoproteins - genetics Nerve Tissue Proteins - metabolism Amyotrophic Lateral Sclerosis - pathology Animals Inflammation - genetics Endosomes - enzymology Mice Mutation Superoxide Dismutase-1 rac1 GTP-Binding Protein Enzyme Activation - genetics Inflammation - enzymology

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