Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss

Wu, T.; Zhu, J.; Strickland, A.; Ko, K. W.; Sasaki, Y.; Dingwall, C.; Yamada, Y.; Figley, M. D.; Mao, X.; Neiner, A.; Bloom, J.; DiAntonio, A.; Milbrandt, J.

doi:10.1101/2021.07.16.452689

bioRxiv · 10.1101/2021.07.16.452689

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss

Wu, T.·Zhu, J.·Strickland, A.·Ko, K. W.·Sasaki, Y.·Dingwall, C.·Yamada, Y.·Figley, M. D.·Mao, X.·Neiner, A.·Bloom, J.·DiAntonio, A.·Milbrandt, J.

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Abstract

SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might also activate SARM1. Here we show that the nicotinamide analogue 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration and neuronal death. Systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to peripheral nerve induces SARM1-dependent axon degeneration. We also identify a related pyridine derivative, 2-aminopyridine, as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and furthermore, suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.

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Wu, T., Zhu, J., Strickland, A., Ko, K. W., Sasaki, Y., Dingwall, C., Yamada, Y., Figley, M. D., Mao, X., Neiner, A., Bloom, J., DiAntonio, A., Milbrandt, J.. 2021-07-16. Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. https://doi.org/10.1101/2021.07.16.452689

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