| First Author | Wu T | Year | 2021 |
| Journal | Cell Rep | Volume | 37 |
| Issue | 3 | Pages | 109872 |
| PubMed ID | 34686345 | Mgi Jnum | J:323592 |
| Mgi Id | MGI:6881820 | Doi | 10.1016/j.celrep.2021.109872 |
| Citation | Wu T, et al. (2021) Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. Cell Rep 37(3):109872 |
| abstractText | 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 activate SARM1. Here, we show the nicotinamide analog 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. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy. |
