Deletion of Sarm1 gene protects against paclitaxel-induced and type II diabetic peripheral neuropathies

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