SARM1 activation and its downstream pathways are distinct in neuronal compartments

Miyamoto, T.; Kim, C.; Chow, J.; Dugas, J. C.; DeGroot, J.; Bagdasarian, A. L.; Thottumkara, A. P.; Larhammar, M.; Calvert, M. E.; Fox, B. M.; Lewcock, J. W.; Kane, L. A.

doi:10.1101/2022.04.27.489702

bioRxiv · 10.1101/2022.04.27.489702

SARM1 activation and its downstream pathways are distinct in neuronal compartments

Miyamoto, T.·Kim, C.·Chow, J.·Dugas, J. C.·DeGroot, J.·Bagdasarian, A. L.·Thottumkara, A. P.·Larhammar, M.·Calvert, M. E.·Fox, B. M.·Lewcock, J. W.·Kane, L. A.

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Abstract

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 mechanisms underlying SARM1s catalytic activity and advanced our understanding of SARM1 function in axons, yet the role of SARM1 signaling in other compartments of neurons is still not well understood. Here we show in cultured hippocampal neurons that endogenous SARM1 is present in axons, dendrites and cell bodies and that direct activation of SARM1 by the neurotoxin Vacor causes not just axon degeneration, but degeneration of all neuronal compartments. In contrast to the axon degeneration pathway defined in dorsal root ganglia (DRGs), SARM1-dependent hippocampal axon degeneration in vitro is not sensitive to calpain inhibition whereas dendrite degeneration downstream of SARM1 is calpain-dependent in this cell type. This data indicates SARM1 plays a critical role in neurodegeneration outside of axons and elucidates divergent pathways leading to degeneration in hippocampal axons and dendrites.

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Miyamoto, T., Kim, C., Chow, J., Dugas, J. C., DeGroot, J., Bagdasarian, A. L., Thottumkara, A. P., Larhammar, M., Calvert, M. E., Fox, B. M., Lewcock, J. W., Kane, L. A.. 2022-04-28. SARM1 activation and its downstream pathways are distinct in neuronal compartments. https://doi.org/10.1101/2022.04.27.489702

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