In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2.
Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation.
This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration.