SARM1 activation and its downstream pathways are distinct in neuronal compartments

Sterile alpha and TIR motif containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD+ following injury. Recent work has defined the structure and catalytic activity of SARM1, yet the specific pathways controlled by SARM1 following diverse neuronal insults are not well defined. Here we show that the mechanisms of SARM1 activation and downstream signaling pathways are both context and localization dependent. Endogenous SARM1 is present in axons, dendrites and cell bodies and is primarily localized to the outer mitochondrial membrane. In cultured hippocampal neurons, knockout of SARM1 protects axons from degeneration by treatment with mitochondrial toxins but does not affect the degeneration of other cell compartments. In contrast, direct activation of SARM1 leads to degeneration of axons, dendrites, and cell bodies, indicating that SARM1 is present and can be activated in these neuronal compartments. Inhibition of dual leucine zipper kinase (DLK, MAP3K12) and caspases were not protective in these paradigms, though both SARM1-dependent and independent dendrite degeneration required calpain activity. Together, these results demonstrate that SARM1 activation is not specific to axons though distinct pathways regulate degeneration in axons and dendrites. ### Competing Interest Statement All authors are paid employees and shareholders of Denali Therapeutics.