NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:25818290, PubMed:26686637, PubMed:27735788, PubMed:32312889). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:21555464, PubMed:22678360, PubMed:25818290, PubMed:26686637, PubMed:26423149). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction (PubMed:28334607). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (By similarity). Can activate neuronal cell death in response to stress (PubMed:19587044). Regulates dendritic arborization through the MAPK4-JNK pathway (PubMed:17724133, PubMed:21555464). Involved in innate immune response: inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38 (PubMed:21555464). H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide NAD(+) = cyclic ADP-ribose + H(+) + nicotinamide H2O + NADP(+) = ADP-D-ribose 2'-phosphate + H(+) + nicotinamide Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats. NAD(+)-binding to ARM repeats maintains an inactive state by promoting interaction between ARM repeats and the TIR domain, thereby facilitating inhibition of the enzymatic TIR domain. Following activation, possibly by nicotinamide mononucleotide (NMN), auto-inhibitory interactions are released, allowing self-association of the TIR domains and subsequent activation of the NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is facilitated by the octamer of SAM domains. Homooctamer; forms an octomeric ring via SAM domains (By similarity). Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF function (By similarity). Interacts with SDC2 (via cytoplasmic domain) and MAPK10/JNK3 (PubMed:17724133, PubMed:21555464). Associated with microtubules. Widely expressed in the brain and neurons (at protein level) (PubMed:21555464). Expressed in photoreceptor cells of the neural retina (PubMed:32312889). Down-regulated in sciatic nerve of mice with diabetic peripheral neuropathy (at protein level). The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. The ARM repeats inhibit the NAD(+) hydrolase (NADase) activity by binding to NAD(+): NAD(+)-binding to ARM repeats facilitates inhibition of the TIR domain NADase through their domain interface. In contrast to classical ARM repeats, the last helix of ARM 6 does not fold back to interact with the first two helices, but instead turns towards the N-terminus of SARM1. As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly. Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones. Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or MAPK10) enhance the NAD(+) hydrolase (NADase) activity. Phosphorylation at Ser-548 and subsequent activation takes place in response to oxidative stress conditions and inhibits mitochondrial respiration. Absence of Sarm1 provides a level of protection against axon degeneration (PubMed:22678360, PubMed:26912636, PubMed:28978465). Genetic deletion blocks Wallerian degeneration of sciatic nerve and cultured superior cervical ganglia and peripheral polyneuropathy induced by vincristine (PubMed:22678360, PubMed:27797810). Severed Sarm1 null axons are able to persist up to 72 hours after axotomy, whereas wild-type axons degenerate within 8 hours (PubMed:22678360). Similarly, axons appear to be protected from degeneration in a sciatic nerve lesion model, lasting up to 14 days compared with 3 days for wild type (PubMed:22678360). Mice display improved traumatic brain injury-associated phenotypes after injury: mice develop fewer beta-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury and show improved axonal integrity (PubMed:26912636). Mice show some protection against early but not late axonal degeneration in experimental allergic encephalomyelitis mouse model (PubMed:32584865). Mice exhibit normal glucose metabolism and pain sensitivity but show attenuated diabetic peripheral neuropathy (PubMed:31439642). Mice lacking both Sarm1 and Nmnat2 are viable and survive: Sarm1 deficiency corrects axon outgrowth in mice lacking Nmnat2, independently of NMNAT metabolites, preventing perinatal lethality (PubMed:25818290). Mice lacking both Rho and Sarm1 show a level of protection against retinal degeneration induced by the absence of Rho: the absence of Sarm1 promoting rod and cone photoreceptor cell survival (PubMed:32312889). Belongs to the SARM1 family.