Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss.
Cell Rep
; 37(3): 109872, 2021 10 19.
Article
en En
| MEDLINE
| ID: mdl-34686345
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Nervio Ciático
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Axones
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Síndromes de Neurotoxicidad
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Proteínas del Citoesqueleto
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Proteínas del Dominio Armadillo
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Ganglios Espinales
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Degeneración Nerviosa
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Neurotoxinas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2021
Tipo del documento:
Article