Abstract SARM1 is a central regulator of programmed axon death and is required to initiate axon self-destruction after traumatic and toxic insults to the nervous system. Abnormal activation of this axon degeneration pathway is increasingly recognized as a contributor to human neurological disease and SARM1 knockdown or inhibition has become an attractive therapeutic strategy to preserve axon loss in a variety of disorders of the peripheral and central nervous system. Despite this, it remains unknown whether Sarm1 /SARM1 is present in myelinating glia and whether it plays a role in myelination in the PNS or CNS. It is important to answer these questions to understand whether future therapies inhibiting SARM1 function may have unintended deleterious impacts on myelination. Here we show that Sarm1 mRNA is present in oligodendrocytes in zebrafish but only detectable at low levels in Schwann cells in both zebrafish and mice. We find SARM1 protein is readily detectable in murine oligodendrocytes in vitro and in vivo and activation of endogenous SARM1 in oligodendrocytes induces cell death. In contrast, SARM1 protein is not detectable in Schwann cells and satellite glia in the adult murine nervous system. Cultured Schwann cells contain negligible functional SARM1 and are insensitive to specific SARM1 activators. Using zebrafish and mouse Sarm1 mutants, we show that SARM1 is not required for initiation of myelination nor myelin sheath maintenance by oligodendrocytes and Schwann cells. Thus, strategies to inhibit SARM1 function in the nervous system to treat neurological disease are unlikely to perturb myelination in humans. Main Points SARM1 protein is detectable in oligodendrocytes but not in Schwann cells Oligodendrocytes but not Schwann cells die in response to endogenous SARM1 activation CNS nor PNS myelination, in zebrafish and mice, is hindered by loss of sarm1/Sarm1

SARM1 detection in oligodendrocytes but not Schwann cells though<i>sarm1/Sarm1</i>deletion does not perturb CNS nor PNS myelination in zebrafish and mice

SARM1 detection in oligodendrocytes but not Schwann cells thoughsarm1/Sarm1deletion does not perturb CNS nor PNS myelination in zebrafish and mice