Abstract

Schwann cells (SCs) transition into a Repair state after peripheral nerve injury, which is crucial for supporting axon regeneration; however, the early SC injury response preceding the repair state remains poorly understood. Here, we demonstrate that Sarm1, a key regulator of axon degeneration, is upregulated in SCs after nerve injury and plays a critical role in the early SC injury response. Using single-nucleus RNA sequencing to compare wild-type and Sarm1 knockout SCs 24 hours after nerve injury, we found that Sarm1-deficient SCs are enriched in a distinct cluster expressing myelination genes (Fth1, Ptgds, Ptprd) that is largely absent in wild-type cells and show increased expression of oxidative phosphorylation and TCA cycle genes across all injured SC states. Functional validation revealed cell type specific Sarm1 knockout SCs displayed increased mitochondrial respiration and enhanced axon protection in in vitro degeneration models, with axon protection also confirmed in an in vivo Drosophila wing injury model. We propose that Sarm1 gates the transition from a protection-associated Schwann cell state (PASC), demarcated by myelin formation genes, to a Repair SC state. These findings challenge the prevailing view of Sarm1 as an exclusively axon-autonomous regulator and reveal its critical role in the SC injury response, with broad implications for treating peripheral neuropathies and neurodegenerative diseases.