Deletion of Sarm1 gene protects against paclitaxel-induced and type II diabetic peripheral neuropathies
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Peripheral sensory neuropathies (PSNs) are disorders of sensory nerve structure and function that impair normal sensation, cause pain, and decrease overall quality of life. Subjects with dietary obesity and pre-diabetes are at a higher risk of developing peripheral sensory neuropathy. Additionally, PSN is a dose-limiting side effect of many commonly prescribed chemotherapeutic drugs such as paclitaxel, a microtubule-stabilizing agent. Molecular pathways leading to distal axon degeneration in chemotherapy-induced peripheral neuropathy and diabetic peripheral neuropathy are mostly unknown. A massive genetic screen in Drosophila identified a role for dSarm in Wallerian degeneration, a well-studied mechanism of axon fragmentation. We hypothesized that Sarm1, the mouse homologue of dSarm, may play a role in axonal degeneration induced by neurotoxic drugs and by increased oxidative stress and glucose intolerance. We found that Sarm1-/- animals display resistance to PSNs induced by paclitaxel and pre-diabetes through behavioral, electrophysiological, and pathological outcome measures of neurotoxicity. This study identifies Sarm1 as a potential key regulator of distal axonal degeneration in multiple disease models of PSN.