{"doi":"10.1016/j.celrep.2021.109872","title":"Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss","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 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.","journal":"Cell Reports","year":2021,"id":163423,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":640716,"name":"Jian Zhu","orcid":"0000-0001-6679-8498","position":1,"is_corresponding":false},{"id":415892,"name":"Amy Strickland","orcid":"0000-0002-5809-8464","position":2,"is_corresponding":false},{"id":262162,"name":"Kwang Woo Ko","orcid":"0000-0003-3813-8913","position":3,"is_corresponding":false},{"id":267988,"name":"Yo Sasaki","orcid":"0000-0003-0024-0031","position":4,"is_corresponding":false},{"id":683163,"name":"Caitlin B. Dingwall","orcid":"0000-0002-2623-0547","position":5,"is_corresponding":false},{"id":389104,"name":"Yurie Yamada","orcid":"0000-0002-0515-1807","position":6,"is_corresponding":false},{"id":256132,"name":"Matthew D. Figley","orcid":"0000-0003-2125-829X","position":7,"is_corresponding":false},{"id":683164,"name":"Xianrong Mao","orcid":"0000-0003-0449-2164","position":8,"is_corresponding":false},{"id":379574,"name":"Alicia Neiner","orcid":null,"position":9,"is_corresponding":false},{"id":683165,"name":"A. Joseph Bloom","orcid":"0000-0002-6731-5539","position":10,"is_corresponding":false},{"id":256133,"name":"Aaron DiAntonio","orcid":"0000-0002-7262-0968","position":11,"is_corresponding":false},{"id":240472,"name":"Jeffrey Milbrandt","orcid":"0000-0002-5477-7689","position":12,"is_corresponding":false},{"id":267990,"name":"Tong Wu","orcid":"0000-0001-9121-2495","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:45:22.477398Z","pmid":"34686345","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}