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

[摘要] 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.

[发布机构] Johns Hopkins University

[效力级别] chemotherapy-induced peripheral neuropathy

[关键词] Peripheral sensory neuropathy;chemotherapy-induced peripheral neuropathy;diabetic polyneuropathy;paclitaxel;taxol;diabetes;pre-diabetes;Wallerian degeneration;nerve conduction studies;intraepidermal nerve fibers;oxidative stress;reactive oxygen species;Biology