{"gene":"SARM1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2006,"finding":"SARM (SARM1) functions as a negative regulator of TRIF-dependent Toll-like receptor signaling; it physically associates with TRIF, and knockdown of endogenous SARM by RNAi enhances TRIF-dependent cytokine and chemokine induction, while SARM overexpression blocks gene induction downstream of TRIF but not MyD88.","method":"Co-immunoprecipitation (SARM–TRIF interaction), RNAi knockdown in human cells, reporter/cytokine assays","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated, RNAi rescue in endogenous system, replicated by multiple subsequent studies","pmids":["16964262"],"is_preprint":false},{"year":2013,"finding":"SARM1 promotes injury-induced axon degeneration; both the SAM and TIR domains are required for this activity. SAM domains mediate SARM1 homo-oligomerization and are necessary and sufficient for SARM–SARM binding, while TIR domain engagement of a downstream destruction pathway is required for degeneration. A construct containing only SAM+TIR elicits degeneration even without injury, and SARM mutants lacking TIR act as dominant negatives. SARM1 associates with neuronal mitochondria, but deletion of the N-terminal mitochondrial localization sequence does not alter pro-degenerative function.","method":"RNAi screen in DRG neurons, domain-deletion and point-mutation analysis, protein–protein interaction (co-IP), live-cell imaging, genetic knockout, dominant-negative overexpression","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, co-IP, genetic KO, dominant-negative), replicated by many subsequent studies","pmids":["23946415"],"is_preprint":false},{"year":2016,"finding":"Dimerization of the SARM1 TIR domain promotes NAD+ consumption and neuronal destruction; this NADase activity is unique to SARM1 among TIR adaptors and is evolutionarily conserved (C. elegans TIR-1 TIR dimerization also causes NAD+ loss). A SARM1-specific 'SS loop' and canonical TIR motifs are required for NAD+ loss and axon degeneration. A residue in the BB loop is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1. A physical interaction between the autoinhibitory N-terminus and the TIR domain of SARM1 was identified, suggesting a direct intramolecular autoinhibitory mechanism.","method":"Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, co-immunoprecipitation (N-terminus–TIR interaction), C. elegans genetic analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro/cellular NAD+ hydrolysis assay with mutagenesis, conserved across species, multiple orthogonal methods","pmids":["27671644"],"is_preprint":false},{"year":2019,"finding":"SARM1 is an injury-activated NAD+ cleavage enzyme (NADase); its intrinsic NADase activity in the TIR domain is essential for its pro-degenerative function. Dominant-negative SARM1 constructs that block NADase activity potently protect axons from degeneration in vitro and in vivo when delivered by AAV.","method":"In vitro NADase assay, AAV-mediated gene delivery, nerve transection model, genetic knockout comparison","journal":"The Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic activity directly measured, in vivo gene therapy validation, multiple orthogonal methods","pmids":["30642945"],"is_preprint":false},{"year":2019,"finding":"SARM1 assembles into a homo-octameric ring; both full-length SARM1 and the isolated tandem SAM1-2 domains form octamers in solution and in crystal lattice. SAM–SAM ring interfaces are mediated by hydrophobic 'lock and key' grooves and electrostatic interactions between neighboring protomers. Mutation of critical SAM oligomerization interfaces reduces SARM1-dependent cell death.","method":"Crystal structure of SAM1-2 domains, electron microscopy of full-length SARM1, size-exclusion chromatography, mutagenesis, cell-death assay","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus solution biophysics plus functional mutagenesis in one study","pmids":["31278906"],"is_preprint":false},{"year":2020,"finding":"NAD+ is an allosteric ligand of the ARM domain of SARM1 that mediates self-inhibition; NAD+ binding to ARM facilitates inhibition of the TIR-domain NADase through the ARM–TIR domain interface. Cryo-EM structures of full-length SARM1 revealed the autoinhibited octameric state. Disruption of the NAD+-binding site or the ARM–TIR interaction causes constitutive SARM1 activation and axonal degeneration.","method":"Cryo-EM (full-length SARM1), in vitro NADase assay, mutagenesis, cellular axon-degeneration assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional mutagenesis in one rigorous study, published in Nature","pmids":["33053563"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) show that both states retain an octameric core; the autoinhibited state features a lock between the ARM domain and the TIR domain. Mutations breaking this ARM–TIR lock activate SARM1 and cannot be further activated by NMN. Active SARM1 is product-inhibited by nicotinamide (NAM). NMN acts as an endogenous activator by disrupting the ARM–TIR lock.","method":"Cryo-EM, in vitro NADase assay, mutagenesis, product-inhibition experiments","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — two cryo-EM states plus biochemical and mutagenesis validation in one study","pmids":["32755591"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM maps of SARM1 at 2.9 and 2.7 Å show that the inactive homo-octamer is stabilized by NAD+ binding at an allosteric site away from the catalytic TIR sites, preventing premature dimerization of catalytic domains. Mutagenesis of this allosteric site causes constitutively active SARM1. NAD+ depletion is proposed to promote disassembly of the peripheral ring and formation of active NADase domain dimers.","method":"Cryo-EM, allosteric site mutagenesis, in vitro NADase assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM with mutagenesis validation, independently replicates NAD+-ARM allosteric model","pmids":["33185189"],"is_preprint":false},{"year":2021,"finding":"SARM1 is activated by an increase in the NMN/NAD+ ratio: NMN and NAD+ compete for binding to the autoinhibitory ARM domain, and NMN binding induces a conformational change that activates SARM1 NADase. Structures of the ARM domain bound to NMN and of the unliganded octameric SARM1 complex were determined. Mutagenesis demonstrated that NMN binding to ARM is required for injury-induced SARM1 activation and axon destruction.","method":"Cryo-EM / X-ray crystallography of ARM–NMN complex, biophysical binding assays, in vitro NADase assay, mutagenesis, cellular axon-degeneration assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural + biochemical + mutagenesis + cellular assays all in one study; corroborates parallel Nature and eLife structures","pmids":["33657413"],"is_preprint":false},{"year":2021,"finding":"Multiple intramolecular and intermolecular domain interfaces are required for SARM1 autoinhibition: ARM–SAM interfaces (intra- and intermolecular), an intermolecular ARM–ARM interface, and two ARM–TIR interfaces (one TIR contacting two distinct ARM domains). Cryo-EM reveals a compact autoinhibited octamer in which TIR domains are isolated. Point mutations in each of five distinct interfaces independently render SARM1 constitutively active.","method":"Cryo-EM of autoinhibited octamer, peptide-mapping/inhibition assay, mutagenesis, in-cell NAD+ measurement, axon-degeneration assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus extensive mutagenesis of five distinct interfaces, multiple orthogonal readouts","pmids":["33468661"],"is_preprint":false},{"year":2015,"finding":"SARM1 acts downstream of NMNAT2 loss in a linear or convergent pathway: axon degeneration induced specifically by NMNAT2 depletion requires SARM1, and SARM1 deficiency corrects both axon degeneration and restricted axon outgrowth in NMNAT2-deficient mice. NAMPT inhibition (reducing NMN) partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation upstream of SARM1.","method":"Genetic epistasis (double Sarm1/Nmnat2 knockout mice), pharmacological NAMPT inhibition, metabolite measurement","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with two orthogonal interventions, replicated by later studies","pmids":["25818290"],"is_preprint":false},{"year":2014,"finding":"Mitochondrial depolarization triggers SARM1-dependent axon degeneration and neuronal cell death in sensory neurons; SARM1 acts downstream of ROS generation (ATP depletion, calcium influx, and ROS accumulation still occur in Sarm1-null neurons, yet death is blocked), defining a SARM1-dependent cell death program termed 'sarmoptosis'.","method":"Pharmacological mitochondrial depolarization (CCCP), Sarm1 genetic knockout, cell-death assays, ROS measurement, ATP measurement, calcium imaging","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean Sarm1-null neurons with multiple biochemical readouts placing SARM1 downstream of ROS; multiple orthogonal methods","pmids":["25009267"],"is_preprint":false},{"year":2013,"finding":"SARM1 forms a complex with PINK1 and TRAF6 on depolarized mitochondria; SARM1 promotes TRAF6-mediated K63-chain ubiquitination of PINK1 at K433, stabilizing PINK1 on the outer mitochondrial membrane and facilitating parkin recruitment for mitophagy. Knockdown of SARM1 or TRAF6 abrogates PINK1 accumulation and parkin recruitment.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mitochondrial fractionation, fluorescence microscopy","journal":"Molecular Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional knockdown in a single lab; not yet independently replicated","pmids":["23885119"],"is_preprint":false},{"year":2012,"finding":"Mitochondria-localized SARM promotes intrinsic apoptosis in T cells during immune activation via ROS generation, mitochondrial depolarization, suppression of Bcl-xL, and downregulation of ERK phosphorylation. The pro-apoptotic function is attributable to the C-terminal SAM and TIR domains. Bcl-xL overexpression and Bax/Bak double-knockout substantially reduce SARM-induced apoptosis.","method":"SARM knockdown/overexpression in T cells, in vivo influenza infection model, Bcl-2 family genetic rescue, caspase activation assay, ROS/mitochondrial potential measurements","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mapping with genetic rescue, single lab, multiple orthogonal methods","pmids":["23175186"],"is_preprint":false},{"year":2019,"finding":"SARM suppresses the NLRP3 inflammasome directly, restraining caspase-1 activation and IL-1β secretion; pyroptosis-inducing NLRP3 stimulants cause SARM-dependent mitochondrial depolarization that distinguishes pyroptotic from hyperactivating stimuli. Sarm1-/- macrophages display increased IL-1β but reduced pyroptosis, and Sarm1-/- mice are protected from LPS-induced sepsis.","method":"Sarm1 genetic knockout macrophages and mice, caspase-1 activation assay, NLRP3 co-IP/functional assay, mitochondrial depolarization measurement, LPS sepsis model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple mechanistic readouts (inflammasome co-IP, caspase-1, mitochondrial potential, in vivo sepsis), multiple orthogonal methods in one study","pmids":["31076360"],"is_preprint":false},{"year":2020,"finding":"TNF-α induces SARM1-dependent axon degeneration via a noncanonical necroptotic signaling mechanism in which MLKL causes loss of axon survival factors NMNAT2 and STMN2, thereby activating SARM1 NADase activity, leading to calcium influx and axon degeneration. MLKL does not directly trigger degeneration in axons; rather it acts upstream of SARM1 through NMNAT2/STMN2 loss.","method":"Genetic knockout (Sarm1, MLKL), siRNA knockdown, NAD+ measurement, calcium imaging, glaucoma neuroinflammation model","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis with multiple KOs, mechanistic biochemical readouts (NAD+, calcium), multiple pathways probed","pmids":["32609299"],"is_preprint":false},{"year":2020,"finding":"cADPR is a product of SARM1-dependent NAD+ cleavage in neurons and nerves in vivo; SARM1 is a major source of cADPR in DRG neurons, sciatic nerve, and brain, and has basal enzymatic activity in healthy tissue. Post-injury cADPR levels increase dramatically in proportion to SARM1 gene dosage, validating cADPR as a SARM1 activity biomarker. Manipulation of cADPR levels does not alter axon degeneration time course, indicating cADPR is not a key effector of degeneration.","method":"Mass spectrometry measurement of cADPR, SARM1 genetic knockout/heterozygous dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes","journal":"Experimental Neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene-dosage series with mass spectrometry quantification, in vitro and in vivo, multiple orthogonal interventions","pmids":["32087251"],"is_preprint":false},{"year":2021,"finding":"Live imaging of single mouse sensory axons shows that SARM1 NADase activity initiates an ordered sequence of events: loss of cellular ATP → defects in mitochondrial movement and depolarization → calcium influx → phosphatidylserine externalization → loss of membrane permeability → catastrophic axon self-destruction.","method":"Live fluorescence imaging of single axons, genetically encoded sensors (ATP, calcium, PS), SARM1 knockout comparison","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — real-time single-axon resolution with multiple orthogonal sensors, genetic controls","pmids":["34779400"],"is_preprint":false},{"year":2021,"finding":"A crystal structure of the Drosophila SARM1 regulatory (ARM) domain complexed with the potent activator VMN (vacor metabolite, an NMN analog) reveals the structural basis for activator binding. VMN is the most potent SARM1 activator known, and SARM1 deletion completely rescues neurons from vacor-induced degeneration in vitro and in vivo.","method":"X-ray crystallography of ARM–VMN complex, genetic Sarm1 knockout, in vitro neuron protection assay, in vivo mouse model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with in vitro and in vivo functional validation","pmids":["34870595"],"is_preprint":false},{"year":2021,"finding":"Nicotinic acid mononucleotide (NaMN) is an allosteric SARM1 inhibitor that competes with NMN for binding to the SARM1 ARM domain allosteric pocket and promotes the open, autoinhibited ARM conformation. Co-crystal structure of NaMN with the ARM domain shows direct binding to the allosteric site, and NaMN-mediated SARM1 inhibition contributes to long-term axon protection.","method":"X-ray crystallography (ARM–NaMN complex), in vitro NADase competition assay, mutagenesis, neuronal axon protection assay","journal":"Experimental Neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical competition assay and mutagenesis in one study","pmids":["34403688"],"is_preprint":false},{"year":2022,"finding":"Tryptoline acrylamide compounds site-specifically and stereoselectively modify cysteine-311 (C311) in the non-catalytic ARM domain of SARM1, allosterically inhibiting NADase activity. C311A/C311S mutants are resistant to inhibition. These covalent inhibitors stereoselectively block vincristine- and vacor-induced neurite degeneration in primary DRG neurons.","method":"Chemical proteomics (activity-based protein profiling), site-directed mutagenesis, in vitro NADase assay, primary neuron degeneration assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical proteomic site identification + mutagenesis abolishing inhibition + cellular functional assay, multiple orthogonal methods","pmids":["35994671"],"is_preprint":false},{"year":2022,"finding":"C. elegans TIR-1/SARM1 undergoes a phase transition (oligomerization into visible puncta) upon physiological stress, and this multimerization dramatically potentiates its NAD+ glycohydrolase activity in vitro. Genetic mutations blocking either multimerization or NADase activity prevent p38/PMK-1 immune pathway activation and increase susceptibility to bacterial infection, placing TIR-1 NADase activity downstream of oligomerization and upstream of p38 MAPK.","method":"Fluorescence imaging of TIR-1–GFP puncta, in vitro enzyme kinetics, C. elegans genetics (loss-of-function mutants, epistasis), p38 phosphorylation assay, infection survival assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of phase-transition-dependent NADase, genetic epistasis, multiple orthogonal methods; C. elegans ortholog of SARM1","pmids":["35098926"],"is_preprint":false},{"year":2022,"finding":"ULK1 (autophagy kinase) physically interacts with SARM1 via SARM1 SAM domains, and this interaction increases upon neurite damage. ULK1 inhibition or Ulk1 knockdown attenuates SARM1 puncta accumulation in neurites and reduces neurite fragmentation. In vivo, axonal ULK1 activation and SARM1 accumulation are both reduced in Beclin1 autophagy hypomorph mice after SCI.","method":"Co-immunoprecipitation (in vitro and in vivo), domain-deletion analysis (SAM domains), ULK1 inhibitor and siRNA knockdown, immunofluorescence, spinal cord injury mouse model","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping plus functional knockdown, single lab, in vivo corroboration","pmids":["36375051"],"is_preprint":false},{"year":2022,"finding":"In C. elegans and mammalian neurons, TIR-1/SARM1 cell-autonomously inhibits axon regeneration by activating the NSY-1/ASK1 MAPK cascade, independently of its NADase activity and degeneration-promoting function. Simultaneously, TIR-1 promotes axon degeneration on the other side of the injury via the DLK-1 MAPK cascade. Human SARM1 also inhibits axon regeneration cell-intrinsically.","method":"C. elegans tir-1 mutants (loss-of-function), NADase-deficient SARM1 variants, epistasis with NSY-1/ASK1 and DLK-1 pathway mutants, human SARM1 expression in C. elegans, axon regeneration imaging","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with NADase-null separation-of-function allele, multiple MAPK pathway mutants, conserved in human SARM1","pmids":["37083456"],"is_preprint":false},{"year":2022,"finding":"SARM1-dependent NAD+ hydrolysis is required for Drosophila neuromuscular junction (NMJ) development: NMJ overgrowth scales with the amount of SARM1 NADase activity, and degenerative and developmental SARM1 signaling use distinct upstream and downstream mechanisms despite sharing the NADase requirement.","method":"Transgenic Drosophila with graded NADase-activity SARM1 variants, NMJ morphometry, genetic epistasis","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — activity-graded transgenic series in Drosophila, single lab, separation-of-function analysis","pmids":["35737728"],"is_preprint":false},{"year":2010,"finding":"SARM inhibits MAPK activation (both TRIF- and MyD88-mediated, and basal) leading to suppression of AP-1, in addition to NF-κB and IRF3. RNAi knockdown of SARM elevates basal AP-1 activity. Truncated SARM changes subcellular localization, indicating that the N-terminal and SAM domains regulate SARM subcellular distribution and activity.","method":"Overexpression and RNAi knockdown, MAPK phosphorylation assay, AP-1 reporter assay, subcellular fractionation/localization","journal":"European Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple pathway assays with RNAi, single lab, localization experiment with truncation mutants","pmids":["20306472"],"is_preprint":false},{"year":2015,"finding":"The BB-loop residue G601 in the SARM TIR domain is essential for SARM's interaction with both MyD88 and TRIF; a G601A mutant loses the ability to suppress LPS-induced IL-8 and TNF-α. A short peptide derived from the BB-loop motif also interacts with MyD88 in vitro, demonstrating that the BB loop mediates SARM–adaptor TIR–TIR interactions.","method":"Recombinant TIR domain interaction assays (in vitro), site-directed mutagenesis (G601A), cytokine reporter assays in HEK293 cells","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — purified protein interaction + mutagenesis + cellular functional assay, single lab","pmids":["26592460"],"is_preprint":false},{"year":2014,"finding":"SARM is required for CCL5 production in macrophages across multiple pattern-recognition pathways (TLR and cytosolic RNA/DNA sensing). SARM acts at the level of the Ccl5 promoter, being critical for recruitment of transcription factors and RNA polymerase II, without affecting MAPK or NF-κB/IRF activation, mRNA stability, or splicing.","method":"Sarm1-/- macrophages, ELISA, chromatin immunoprecipitation (transcription factor and Pol II at Ccl5 promoter), RT-PCR, cytokine profiling","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP mechanistic evidence plus genetic KO, single lab, novel transcriptional role","pmids":["24711619"],"is_preprint":false},{"year":2018,"finding":"NLRX1 associates with SARM1 at the mitochondrial matrix in non-neuronal cells; in these cells, the apoptotic role of NLRX1 is fully dependent on SARM1, placing SARM1 downstream of NLRX1 in apoptosis regulation. Wallerian degeneration in primary neurons occurs in a SARM1-dependent but NLRX1-independent manner, indicating that different SARM1 subcellular pools mediate distinct functions.","method":"Co-immunoprecipitation (endogenous NLRX1–SARM1), mitochondrial fractionation, siRNA knockdown, Sarm1-/- neurons, cell-death assay","journal":"Molecular and Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — endogenous co-IP with functional knockdown, single lab, fractionation supports localization","pmids":["30191480"],"is_preprint":false},{"year":2013,"finding":"UXT isoforms differentially regulate SARM-induced apoptosis: UXT V1 reduces caspase-8 activity (anti-apoptotic), while UXT V2 strongly increases caspase-8 and enhances SARM-induced apoptosis via the extrinsic pathway and mitochondrial depolarization. Both isoforms interact with SARM by yeast two-hybrid analysis.","method":"Yeast two-hybrid (UXT–SARM interaction), overexpression, caspase-8 activity assay, mitochondrial depolarization measurement","journal":"FEBS Letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid interaction plus overexpression assays, single lab, no endogenous co-IP","pmids":["24021647"],"is_preprint":false},{"year":2022,"finding":"A nanobody (Nb-C6) specifically recognizes NMN-activated SARM1. Cryo-EM of the NMN/SARM1/Nb-C6 complex reveals an octameric structure in which ARM domains bend significantly inward and swing outward together with TIR domains upon activation. Nb-C6 binds the SAM domain of activated SARM1. Mass spectrometry indicates that activated SARM1 in solution is highly dynamic, with neighboring TIRs forming transient dimers via the BB-loop surface.","method":"Nanobody generation, cryo-EM of activated SARM1 complex, native mass spectrometry, hydrogen–deuterium exchange MS","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of activated state plus native MS dynamics, orthogonal structural methods","pmids":["36550129"],"is_preprint":false},{"year":2021,"finding":"Acidic pH (protonation of negative residues) activates SARM1 enzymatic activity even more efficiently than NMN. Mutagenesis revealed: E689Q in TIR constitutively activates SARM1 by disrupting a salt bridge with R216 in ARM that maintains autoinhibition; K597E inhibits activation; H685A eliminates catalytic activity. Distinct classes of chemical inhibitors act either by blocking activation (NAD, dHNN, disulfiram) or by inhibiting catalysis (nicotinamide, Tweens).","method":"In vitro NADase assay at varying pH, systematic site-directed mutagenesis, inhibitor classification","journal":"The FEBS Journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with systematic mutagenesis, single lab","pmids":["34213829"],"is_preprint":false},{"year":2020,"finding":"Cysteines 629 and 635 in the SARM1 TIR domain are critical for SARM1 catalysis; site-directed mutagenesis of these residues abolishes or reduces NADase activity. Zinc chloride inhibits SARM1 in a noncompetitive manner, suggesting an allosteric binding pocket on SARM1.","method":"High-throughput NADase screen, noncompetitive inhibition kinetics, site-directed mutagenesis (C629 and C635)","journal":"Bioorganic & Medicinal Chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis identifying catalytic cysteines, single lab","pmids":["32828421"],"is_preprint":false},{"year":2022,"finding":"In C. elegans, CaMKII/UNC-43 activates the conserved Sarm1/TIR-1–ASK1/NSY-1–p38 MAPK pathway to protect against axon degeneration caused by loss of mitochondria. Disruption of a trafficking complex (calsyntenin/CASY-1, Mint/LIN-10, kinesin) activates this CaMKII–Sarm1–MAPK neuroprotective pathway through L-type voltage-gated calcium channels.","method":"Unbiased genetic screen, C. elegans genetics (loss-of-function and epistasis), in vivo axon imaging","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased genetic screen plus epistasis in C. elegans, single lab; SARM1 ortholog context","pmids":["35285800"],"is_preprint":false},{"year":2023,"finding":"TRPV1 interacts with SARM1 via TRPV1's N-terminal ankyrin repeat domain binding to the TIR-His583 domain of SARM1. This interaction, confirmed by co-IP, SPR, BRET, and NanoBiT, is required for TRPV1 to maintain hepatic stellate cell quiescence and prevent NF-κB-dependent pro-inflammatory activation and liver fibrosis.","method":"Mass spectrometry (interactome), co-immunoprecipitation, surface plasmon resonance, BRET, NanoBiT bioluminescence proximity assay, domain-mapping, Trpv1-/- mice","journal":"Journal of Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (SPR, BRET, NanoBiT, co-IP) plus in vivo KO, single lab","pmids":["36669703"],"is_preprint":false},{"year":2024,"finding":"Human SARM1 regulates proinflammatory cytokines in monocytes through both NADase-dependent and NADase-independent mechanisms: TNF mRNA induction is negatively regulated independently of NADase activity, while IL-1β secretion is inhibited via NADase-dependent suppression of pro-IL-1β expression AND via NADase-independent suppression of NLRP3 inflammasome processing.","method":"SARM1 knockout human monocytes, NADase-inactive SARM1 mutant, TLR4 stimulation, ELISA, RT-PCR, NLRP3 inflammasome assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus separation-of-function NADase mutant in human cells, single lab, multiple readouts","pmids":["38832024"],"is_preprint":false},{"year":2015,"finding":"SAG-dependent ubiquitin-proteasome system (UPS) targets SARM1 for ubiquitination and proteasomal degradation in hepatocellular carcinoma; upregulated SAG promotes high-molecular-weight ubiquitination of SARM1 (and Noxa), reducing their levels. SARM1 overexpression activates caspase-3 and caspase-9, reducing HCC cell viability.","method":"Co-IP of ubiquitinated SARM1, SAG overexpression/knockdown, caspase activation assay, HCC tissue immunohistochemistry","journal":"Cell Death Discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP ubiquitination without reconstituted E3 assay, correlative tissue data","pmids":["27551463"],"is_preprint":false},{"year":2022,"finding":"In a rat CMT2A model (Mfn2H361Y), deletion of Sarm1 rescues axonal, synaptic, muscle, and functional phenotypes, and also suppresses mitochondrial defects (number, size, cristae density) caused by the MFN2 mutation, revealing a positive feedback loop in which dysfunctional mitochondria activate SARM1 and activated SARM1 feeds back to exacerbate mitochondrial pathology.","method":"Sarm1-/- × Mfn2H361Y double-mutant rat model, neuromuscular junction histology, electron microscopy (mitochondria), behavioral testing","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double-mutant rat model with multiple orthogonal phenotypic readouts; feedback loop established by genetic rescue","pmids":["36287202"],"is_preprint":false}],"current_model":"SARM1 is an NAD+-cleaving enzyme (NADase) whose activity resides in its TIR domain and is normally held in check by an autoinhibited homo-octameric structure in which NAD+ bound to the N-terminal ARM domain locks the TIR domains apart; axon injury or disease increases the NMN/NAD+ ratio, causing NMN to displace NAD+ from the ARM allosteric site, relieving autoinhibition and allowing TIR dimerization, catastrophic NAD+ depletion, ATP loss, calcium influx, and programmed axon self-destruction (Wallerian degeneration), while in innate immune cells SARM1 negatively regulates TLR/TRIF signaling, suppresses NLRP3 inflammasome-dependent IL-1β and pyroptosis, and modulates macrophage NAD+ metabolism through both NADase-dependent and -independent mechanisms."},"narrative":{"mechanistic_narrative":"SARM1 is an injury-activated NAD+-cleaving enzyme that functions as the central executioner of programmed axon self-destruction (Wallerian degeneration) and additionally serves as a regulator of innate immune signaling [PMID:30642945, PMID:16964262]. The protein assembles into an autoinhibited homo-octameric ring built from SAM-domain 'lock and key' interfaces, with the catalytic TIR domains held isolated and inactive by NAD+ bound at an allosteric site in the N-terminal ARM domain and by multiple intramolecular ARM–TIR locks [PMID:31278906, PMID:33053563, PMID:33185189, PMID:33468661]. Axon injury raises the NMN/NAD+ ratio; NMN competes with NAD+ at the ARM allosteric pocket, breaks the ARM–TIR lock, and triggers the conformational change that frees the TIR domains to dimerize and consume NAD+ catastrophically [PMID:32755591, PMID:33657413, PMID:36550129]. The NADase activity, which resides in the TIR domain and depends on conserved catalytic residues, is essential for degeneration: forced TIR dimerization causes NAD+ loss and neuronal death, and NADase-dead or dominant-negative constructs protect axons in vitro and in vivo [PMID:27671644, PMID:30642945, PMID:32828421]. Downstream, SARM1 NADase activity initiates an ordered collapse — ATP loss, mitochondrial depolarization, calcium influx, phosphatidylserine externalization, and membrane rupture [PMID:34779400, PMID:25009267]. SARM1 acts genetically downstream of loss of the axon survival factor NMNAT2, and diverse insults including mitochondrial depolarization, TNF-driven noncanonical necroptosis (via MLKL-dependent NMNAT2/STMN2 loss), and the neurotoxin vacor converge on this NMN/NAD+-sensing switch [PMID:25818290, PMID:25009267, PMID:32609299, PMID:34870595]. The pathway is pharmacologically tractable: NaMN is an endogenous allosteric inhibitor, and covalent ligands targeting ARM cysteine C311 block degeneration [PMID:34403688, PMID:35994671]. Genetic deletion of Sarm1 rescues axonal, synaptic, and mitochondrial pathology in a CMT2A (Mfn2) model, defining a feedback loop between mitochondrial dysfunction and SARM1 activation [PMID:36287202]. Separately, SARM1 negatively regulates TRIF-dependent TLR signaling and restrains the NLRP3 inflammasome to suppress IL-1β and pyroptosis through both NADase-dependent and NADase-independent mechanisms [PMID:16964262, PMID:31076360, PMID:38832024].","teleology":[{"year":2006,"claim":"Established the first molecular function of SARM1, identifying it as a negative regulator that physically engages the TLR adaptor TRIF, defining a role outside the nervous system.","evidence":"Co-IP of SARM–TRIF and RNAi knockdown with cytokine reporters in human cells","pmids":["16964262"],"confidence":"High","gaps":["Did not define the structural basis of TRIF binding","Did not address any neuronal function"]},{"year":2013,"claim":"Defined SARM1 as a pro-degenerative factor and mapped the SAM domains to oligomerization and the TIR domain to engagement of a destruction pathway, framing the modular logic of the protein.","evidence":"RNAi screen in DRG neurons with domain-deletion/point mutants, co-IP, genetic KO, and dominant-negative overexpression","pmids":["23946415"],"confidence":"High","gaps":["Enzymatic identity of the TIR domain not yet known","Activating signal upstream not defined"]},{"year":2014,"claim":"Placed SARM1 downstream of ROS and mitochondrial depolarization in a distinct neuronal death program, ordering it within the degeneration cascade.","evidence":"CCCP depolarization with Sarm1-null neurons, ROS/ATP/calcium readouts","pmids":["25009267"],"confidence":"High","gaps":["Molecular sensor linking depolarization to SARM1 not identified","Catalytic mechanism still unknown at this stage"]},{"year":2015,"claim":"Established genetic epistasis showing SARM1 acts downstream of NMNAT2 loss, linking axon survival-factor turnover to a SARM1-dependent destruction pathway.","evidence":"Double Sarm1/Nmnat2 knockout mice with NAMPT inhibition and metabolite measurement","pmids":["25818290"],"confidence":"High","gaps":["Did not establish NMN as the direct activating ligand","Mechanism connecting NMNAT2 loss to SARM1 activity not resolved"]},{"year":2016,"claim":"Identified the TIR domain as the source of NAD+-consuming activity unique among TIR adaptors and conserved to C. elegans, recasting SARM1 as an enzyme rather than a scaffold.","evidence":"Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, N-terminus–TIR co-IP, C. elegans genetics","pmids":["27671644"],"confidence":"High","gaps":["Did not directly measure purified-enzyme NADase kinetics","Structural basis of autoinhibition not yet solved"]},{"year":2019,"claim":"Directly demonstrated injury-activated intrinsic NADase activity is essential for degeneration and that blocking it is axon-protective in vivo, validating SARM1 as a therapeutic target.","evidence":"In vitro NADase assay, AAV delivery of dominant-negative constructs, nerve transection, KO comparison","pmids":["30642945"],"confidence":"High","gaps":["Did not resolve the allosteric activation mechanism","Octameric architecture not yet defined"]},{"year":2019,"claim":"Solved the octameric ring architecture and mapped SAM–SAM interfaces, providing the structural unit of SARM1 assembly.","evidence":"Crystal structure of SAM1-2, EM of full-length protein, SEC, mutagenesis, cell-death assay","pmids":["31278906"],"confidence":"High","gaps":["Did not capture the autoinhibitory ARM–TIR contacts","Did not define the activating ligand"]},{"year":2020,"claim":"Converging cryo-EM studies established that NAD+ binding to the ARM domain enforces an autoinhibited octamer that locks TIR domains apart, with NMN acting as an endogenous activator that disrupts the ARM–TIR lock.","evidence":"Multiple cryo-EM structures of autoinhibited and active states, NADase assays, product-inhibition, and interface mutagenesis (Nature, Cell Reports, eLife)","pmids":["33053563","32755591","33185189"],"confidence":"High","gaps":["Atomic-resolution NMN-bound activated catalytic site not fully resolved","Dynamics of TIR dimerization during catalysis incompletely defined"]},{"year":2020,"claim":"Identified cADPR as an in vivo product of SARM1 NAD+ cleavage and a quantitative biomarker, while showing it is not the effector of degeneration.","evidence":"Mass spectrometry, Sarm1 gene-dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes","pmids":["32087251"],"confidence":"High","gaps":["The metabolic consequence driving degeneration (vs cADPR) not isolated here","Basal physiological role of constitutive activity unclear"]},{"year":2021,"claim":"Established the NMN/NAD+ ratio as the activating signal through competitive ARM-domain binding, unifying the metabolic trigger with the structural switch.","evidence":"Cryo-EM/crystallography of ARM–NMN, biophysical binding, NADase assays, mutagenesis, cellular degeneration; plus mapping of five autoinhibitory interfaces","pmids":["33657413","33468661"],"confidence":"High","gaps":["In vivo dynamics of NMN/NAD+ sensing during injury not directly imaged","How multiple interfaces release sequentially not resolved"]},{"year":2021,"claim":"Resolved the temporal order of downstream destruction events at single-axon resolution, placing NADase activity at the apex of an ATP→mitochondrial→calcium→membrane cascade.","evidence":"Live imaging of single sensory axons with genetically encoded ATP/calcium/PS sensors and KO controls","pmids":["34779400"],"confidence":"High","gaps":["Molecular link from NAD+ loss to calcium influx not pinned to specific channels","PS-externalization machinery not identified"]},{"year":2021,"claim":"Expanded the activator/inhibitor pharmacology by structurally defining the potent activator VMN and the endogenous inhibitor NaMN at the ARM allosteric pocket, plus pH and salt-bridge determinants of activation.","evidence":"Crystal structures of ARM–VMN and ARM–NaMN, NADase competition assays, mutagenesis (E689/R216 salt bridge), neuron protection","pmids":["34870595","34403688","34213829"],"confidence":"High","gaps":["NaMN-based therapeutic window in vivo not established here","Physiological relevance of pH activation not defined"]},{"year":2022,"claim":"Identified druggable allosteric and catalytic sites (covalent C311 ligands, catalytic cysteines, zinc) enabling small-molecule inhibition of degeneration.","evidence":"Chemical proteomics with C311 mutagenesis and DRG degeneration assays; high-throughput NADase screen with C629/C635 mutagenesis","pmids":["35994671","32828421"],"confidence":"High","gaps":["In vivo efficacy and selectivity of covalent inhibitors not fully established","Relationship between catalytic cysteines and the NAD+ catalytic mechanism not structurally resolved"]},{"year":2022,"claim":"Captured the activated, conformationally dynamic state by cryo-EM and native MS, showing ARM inward bending and transient BB-loop-mediated TIR dimers as the catalytic species.","evidence":"Activation-state-specific nanobody, cryo-EM of NMN/SARM1/Nb-C6, native MS and HDX-MS","pmids":["36550129"],"confidence":"High","gaps":["High-resolution structure of the catalytically competent TIR dimer not solved","Whether the octamer disassembles or remains intact during catalysis debated"]},{"year":2022,"claim":"Showed SARM1 activation drives disease in a CMT2A mitochondrial-mutation model, with Sarm1 deletion rescuing both axonal and mitochondrial pathology, establishing a degenerative feedback loop.","evidence":"Sarm1-/- × Mfn2H361Y double-mutant rat model with NMJ histology, EM, and behavior","pmids":["36287202"],"confidence":"High","gaps":["Did not define the molecular signal from mutant mitochondria to SARM1","Generalizability to other CMT subtypes not tested"]},{"year":2023,"claim":"Demonstrated that SARM1 NADase activity also drives non-degenerative developmental and immune phenotypes (Drosophila NMJ growth; C. elegans p38/PMK-1 innate immunity via stress-induced phase transition), distinguishing degenerative from physiological signaling.","evidence":"Graded-NADase transgenic Drosophila and C. elegans TIR-1 imaging/enzymology with infection assays","pmids":["35737728","35098926"],"confidence":"High","gaps":["Whether mammalian SARM1 supports analogous developmental NADase signaling not shown","Effectors linking NADase output to p38/MAPK not defined"]},{"year":2023,"claim":"Resolved a NADase-independent arm of SARM1 function in axon regeneration via MAPK cascades, separating its scaffolding/signaling roles from its enzymatic destruction role.","evidence":"C. elegans tir-1 mutants and NADase-deficient SARM1 with NSY-1/ASK1 and DLK-1 epistasis, human SARM1 in worms","pmids":["37083456"],"confidence":"High","gaps":["Mammalian regeneration role of SARM1 not fully mapped","Molecular partners coupling SARM1 to ASK1/DLK1 not identified"]},{"year":2024,"claim":"Dissected the dual NADase-dependent and -independent immune functions in human cells, showing TNF and IL-1β are controlled through distinct enzymatic and non-enzymatic routes.","evidence":"SARM1-KO human monocytes with NADase-inactive mutant, TLR4 stimulation, ELISA/RT-PCR, NLRP3 assay","pmids":["38832024"],"confidence":"Medium","gaps":["Direct molecular targets of the NADase-independent suppression not identified","Single-lab finding in monocytes; in vivo relevance not established"]},{"year":null,"claim":"How the same NMN/NAD+-sensing enzyme is wired to opposing outcomes — axon destruction, axon regeneration inhibition, developmental NMJ growth, and immune regulation — across cell types and subcellular pools remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Subcellular pools (mitochondrial vs cytosolic) directing distinct functions not fully mapped","The effectors translating NAD+ loss into calcium influx and membrane breakdown are unidentified","How non-enzymatic SARM1 signaling engages MAPK and immune pathways mechanistically is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,3,5,16,32]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,16]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,8,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,14]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,11,12,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,25]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,13,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,8,16,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,14,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,25,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[23,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[37,18]}],"complexes":["SARM1 homo-octamer","SARM1–PINK1–TRAF6 mitochondrial complex"],"partners":["TRIF","PINK1","TRAF6","NLRX1","ULK1","TRPV1","MYD88","UXT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6SZW1","full_name":"NAD(+) hydrolase SARM1","aliases":["NADP(+) hydrolase SARM1","Sterile alpha and Armadillo repeat protein","Sterile alpha and TIR motif-containing protein 1","Sterile alpha motif domain-containing protein 2","MyD88-5","SAM domain-containing protein 2","Tir-1 homolog","HsTIR"],"length_aa":724,"mass_kda":79.4,"function":"NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:25908823, PubMed:27671644, PubMed:28334607). 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:15123841, PubMed:16964262, PubMed:20306472, PubMed:25908823). 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:25908823, PubMed:28334607, PubMed:30333228, PubMed:31128467, PubMed:31439792, PubMed:31439793, PubMed:32049506, PubMed:32828421, PubMed:33053563). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (PubMed:29395922). Can activate neuronal cell death in response to stress (PubMed:20306472). Regulates dendritic arborization through the MAPK4-JNK pathway (By similarity). 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:16964262)","subcellular_location":"Cytoplasm; Cell projection, axon; Cell projection, dendrite; Synapse; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q6SZW1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SARM1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":77,"dependency_fraction":0.025974025974025976},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SARM1","total_profiled":1310},"omim":[{"mim_id":"608700","title":"NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1","url":"https://www.omim.org/entry/608700"},{"mim_id":"608507","title":"MITOFUSIN 2; MFN2","url":"https://www.omim.org/entry/608507"},{"mim_id":"607732","title":"STERILE ALPHA AND TIR MOTIFS-CONTAINING PROTEIN 1; SARM1","url":"https://www.omim.org/entry/607732"},{"mim_id":"606717","title":"XIAP-ASSOCIATED FACTOR 1; XAF1","url":"https://www.omim.org/entry/606717"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SARM1"},"hgnc":{"alias_symbol":["SARM","SAMD2","KIAA0524"],"prev_symbol":[]},"alphafold":{"accession":"Q6SZW1","domains":[{"cath_id":"-","chopping":"303-404","consensus_level":"medium","plddt":90.8833,"start":303,"end":404},{"cath_id":"-","chopping":"408-545","consensus_level":"medium","plddt":96.1811,"start":408,"end":545},{"cath_id":"3.40.50.10140","chopping":"563-697","consensus_level":"high","plddt":89.4587,"start":563,"end":697}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6SZW1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6SZW1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6SZW1-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SARM1","jax_strain_url":"https://www.jax.org/strain/search?query=SARM1"},"sequence":{"accession":"Q6SZW1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6SZW1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6SZW1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6SZW1"}},"corpus_meta":[{"pmid":"16964262","id":"PMC_16964262","title":"The 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negative regulator of TRIF-dependent Toll-like receptor signaling; it physically associates with TRIF, and knockdown of endogenous SARM by RNAi enhances TRIF-dependent cytokine and chemokine induction, while SARM overexpression blocks gene induction downstream of TRIF but not MyD88.\",\n      \"method\": \"Co-immunoprecipitation (SARM–TRIF interaction), RNAi knockdown in human cells, reporter/cytokine assays\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction demonstrated, RNAi rescue in endogenous system, replicated by multiple subsequent studies\",\n      \"pmids\": [\"16964262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SARM1 promotes injury-induced axon degeneration; both the SAM and TIR domains are required for this activity. SAM domains mediate SARM1 homo-oligomerization and are necessary and sufficient for SARM–SARM binding, while TIR domain engagement of a downstream destruction pathway is required for degeneration. A construct containing only SAM+TIR elicits degeneration even without injury, and SARM mutants lacking TIR act as dominant negatives. SARM1 associates with neuronal mitochondria, but deletion of the N-terminal mitochondrial localization sequence does not alter pro-degenerative function.\",\n      \"method\": \"RNAi screen in DRG neurons, domain-deletion and point-mutation analysis, protein–protein interaction (co-IP), live-cell imaging, genetic knockout, dominant-negative overexpression\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, co-IP, genetic KO, dominant-negative), replicated by many subsequent studies\",\n      \"pmids\": [\"23946415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dimerization of the SARM1 TIR domain promotes NAD+ consumption and neuronal destruction; this NADase activity is unique to SARM1 among TIR adaptors and is evolutionarily conserved (C. elegans TIR-1 TIR dimerization also causes NAD+ loss). A SARM1-specific 'SS loop' and canonical TIR motifs are required for NAD+ loss and axon degeneration. A residue in the BB loop is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1. A physical interaction between the autoinhibitory N-terminus and the TIR domain of SARM1 was identified, suggesting a direct intramolecular autoinhibitory mechanism.\",\n      \"method\": \"Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, co-immunoprecipitation (N-terminus–TIR interaction), C. elegans genetic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro/cellular NAD+ hydrolysis assay with mutagenesis, conserved across species, multiple orthogonal methods\",\n      \"pmids\": [\"27671644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SARM1 is an injury-activated NAD+ cleavage enzyme (NADase); its intrinsic NADase activity in the TIR domain is essential for its pro-degenerative function. Dominant-negative SARM1 constructs that block NADase activity potently protect axons from degeneration in vitro and in vivo when delivered by AAV.\",\n      \"method\": \"In vitro NADase assay, AAV-mediated gene delivery, nerve transection model, genetic knockout comparison\",\n      \"journal\": \"The Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic activity directly measured, in vivo gene therapy validation, multiple orthogonal methods\",\n      \"pmids\": [\"30642945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SARM1 assembles into a homo-octameric ring; both full-length SARM1 and the isolated tandem SAM1-2 domains form octamers in solution and in crystal lattice. SAM–SAM ring interfaces are mediated by hydrophobic 'lock and key' grooves and electrostatic interactions between neighboring protomers. Mutation of critical SAM oligomerization interfaces reduces SARM1-dependent cell death.\",\n      \"method\": \"Crystal structure of SAM1-2 domains, electron microscopy of full-length SARM1, size-exclusion chromatography, mutagenesis, cell-death assay\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus solution biophysics plus functional mutagenesis in one study\",\n      \"pmids\": [\"31278906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NAD+ is an allosteric ligand of the ARM domain of SARM1 that mediates self-inhibition; NAD+ binding to ARM facilitates inhibition of the TIR-domain NADase through the ARM–TIR domain interface. Cryo-EM structures of full-length SARM1 revealed the autoinhibited octameric state. Disruption of the NAD+-binding site or the ARM–TIR interaction causes constitutive SARM1 activation and axonal degeneration.\",\n      \"method\": \"Cryo-EM (full-length SARM1), in vitro NADase assay, mutagenesis, cellular axon-degeneration assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional mutagenesis in one rigorous study, published in Nature\",\n      \"pmids\": [\"33053563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) show that both states retain an octameric core; the autoinhibited state features a lock between the ARM domain and the TIR domain. Mutations breaking this ARM–TIR lock activate SARM1 and cannot be further activated by NMN. Active SARM1 is product-inhibited by nicotinamide (NAM). NMN acts as an endogenous activator by disrupting the ARM–TIR lock.\",\n      \"method\": \"Cryo-EM, in vitro NADase assay, mutagenesis, product-inhibition experiments\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two cryo-EM states plus biochemical and mutagenesis validation in one study\",\n      \"pmids\": [\"32755591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM maps of SARM1 at 2.9 and 2.7 Å show that the inactive homo-octamer is stabilized by NAD+ binding at an allosteric site away from the catalytic TIR sites, preventing premature dimerization of catalytic domains. Mutagenesis of this allosteric site causes constitutively active SARM1. NAD+ depletion is proposed to promote disassembly of the peripheral ring and formation of active NADase domain dimers.\",\n      \"method\": \"Cryo-EM, allosteric site mutagenesis, in vitro NADase assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM with mutagenesis validation, independently replicates NAD+-ARM allosteric model\",\n      \"pmids\": [\"33185189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARM1 is activated by an increase in the NMN/NAD+ ratio: NMN and NAD+ compete for binding to the autoinhibitory ARM domain, and NMN binding induces a conformational change that activates SARM1 NADase. Structures of the ARM domain bound to NMN and of the unliganded octameric SARM1 complex were determined. Mutagenesis demonstrated that NMN binding to ARM is required for injury-induced SARM1 activation and axon destruction.\",\n      \"method\": \"Cryo-EM / X-ray crystallography of ARM–NMN complex, biophysical binding assays, in vitro NADase assay, mutagenesis, cellular axon-degeneration assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural + biochemical + mutagenesis + cellular assays all in one study; corroborates parallel Nature and eLife structures\",\n      \"pmids\": [\"33657413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Multiple intramolecular and intermolecular domain interfaces are required for SARM1 autoinhibition: ARM–SAM interfaces (intra- and intermolecular), an intermolecular ARM–ARM interface, and two ARM–TIR interfaces (one TIR contacting two distinct ARM domains). Cryo-EM reveals a compact autoinhibited octamer in which TIR domains are isolated. Point mutations in each of five distinct interfaces independently render SARM1 constitutively active.\",\n      \"method\": \"Cryo-EM of autoinhibited octamer, peptide-mapping/inhibition assay, mutagenesis, in-cell NAD+ measurement, axon-degeneration assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus extensive mutagenesis of five distinct interfaces, multiple orthogonal readouts\",\n      \"pmids\": [\"33468661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SARM1 acts downstream of NMNAT2 loss in a linear or convergent pathway: axon degeneration induced specifically by NMNAT2 depletion requires SARM1, and SARM1 deficiency corrects both axon degeneration and restricted axon outgrowth in NMNAT2-deficient mice. NAMPT inhibition (reducing NMN) partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation upstream of SARM1.\",\n      \"method\": \"Genetic epistasis (double Sarm1/Nmnat2 knockout mice), pharmacological NAMPT inhibition, metabolite measurement\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with two orthogonal interventions, replicated by later studies\",\n      \"pmids\": [\"25818290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mitochondrial depolarization triggers SARM1-dependent axon degeneration and neuronal cell death in sensory neurons; SARM1 acts downstream of ROS generation (ATP depletion, calcium influx, and ROS accumulation still occur in Sarm1-null neurons, yet death is blocked), defining a SARM1-dependent cell death program termed 'sarmoptosis'.\",\n      \"method\": \"Pharmacological mitochondrial depolarization (CCCP), Sarm1 genetic knockout, cell-death assays, ROS measurement, ATP measurement, calcium imaging\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean Sarm1-null neurons with multiple biochemical readouts placing SARM1 downstream of ROS; multiple orthogonal methods\",\n      \"pmids\": [\"25009267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SARM1 forms a complex with PINK1 and TRAF6 on depolarized mitochondria; SARM1 promotes TRAF6-mediated K63-chain ubiquitination of PINK1 at K433, stabilizing PINK1 on the outer mitochondrial membrane and facilitating parkin recruitment for mitophagy. Knockdown of SARM1 or TRAF6 abrogates PINK1 accumulation and parkin recruitment.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mitochondrial fractionation, fluorescence microscopy\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional knockdown in a single lab; not yet independently replicated\",\n      \"pmids\": [\"23885119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mitochondria-localized SARM promotes intrinsic apoptosis in T cells during immune activation via ROS generation, mitochondrial depolarization, suppression of Bcl-xL, and downregulation of ERK phosphorylation. The pro-apoptotic function is attributable to the C-terminal SAM and TIR domains. Bcl-xL overexpression and Bax/Bak double-knockout substantially reduce SARM-induced apoptosis.\",\n      \"method\": \"SARM knockdown/overexpression in T cells, in vivo influenza infection model, Bcl-2 family genetic rescue, caspase activation assay, ROS/mitochondrial potential measurements\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mapping with genetic rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23175186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SARM suppresses the NLRP3 inflammasome directly, restraining caspase-1 activation and IL-1β secretion; pyroptosis-inducing NLRP3 stimulants cause SARM-dependent mitochondrial depolarization that distinguishes pyroptotic from hyperactivating stimuli. Sarm1-/- macrophages display increased IL-1β but reduced pyroptosis, and Sarm1-/- mice are protected from LPS-induced sepsis.\",\n      \"method\": \"Sarm1 genetic knockout macrophages and mice, caspase-1 activation assay, NLRP3 co-IP/functional assay, mitochondrial depolarization measurement, LPS sepsis model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple mechanistic readouts (inflammasome co-IP, caspase-1, mitochondrial potential, in vivo sepsis), multiple orthogonal methods in one study\",\n      \"pmids\": [\"31076360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TNF-α induces SARM1-dependent axon degeneration via a noncanonical necroptotic signaling mechanism in which MLKL causes loss of axon survival factors NMNAT2 and STMN2, thereby activating SARM1 NADase activity, leading to calcium influx and axon degeneration. MLKL does not directly trigger degeneration in axons; rather it acts upstream of SARM1 through NMNAT2/STMN2 loss.\",\n      \"method\": \"Genetic knockout (Sarm1, MLKL), siRNA knockdown, NAD+ measurement, calcium imaging, glaucoma neuroinflammation model\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis with multiple KOs, mechanistic biochemical readouts (NAD+, calcium), multiple pathways probed\",\n      \"pmids\": [\"32609299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"cADPR is a product of SARM1-dependent NAD+ cleavage in neurons and nerves in vivo; SARM1 is a major source of cADPR in DRG neurons, sciatic nerve, and brain, and has basal enzymatic activity in healthy tissue. Post-injury cADPR levels increase dramatically in proportion to SARM1 gene dosage, validating cADPR as a SARM1 activity biomarker. Manipulation of cADPR levels does not alter axon degeneration time course, indicating cADPR is not a key effector of degeneration.\",\n      \"method\": \"Mass spectrometry measurement of cADPR, SARM1 genetic knockout/heterozygous dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes\",\n      \"journal\": \"Experimental Neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene-dosage series with mass spectrometry quantification, in vitro and in vivo, multiple orthogonal interventions\",\n      \"pmids\": [\"32087251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Live imaging of single mouse sensory axons shows that SARM1 NADase activity initiates an ordered sequence of events: loss of cellular ATP → defects in mitochondrial movement and depolarization → calcium influx → phosphatidylserine externalization → loss of membrane permeability → catastrophic axon self-destruction.\",\n      \"method\": \"Live fluorescence imaging of single axons, genetically encoded sensors (ATP, calcium, PS), SARM1 knockout comparison\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — real-time single-axon resolution with multiple orthogonal sensors, genetic controls\",\n      \"pmids\": [\"34779400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A crystal structure of the Drosophila SARM1 regulatory (ARM) domain complexed with the potent activator VMN (vacor metabolite, an NMN analog) reveals the structural basis for activator binding. VMN is the most potent SARM1 activator known, and SARM1 deletion completely rescues neurons from vacor-induced degeneration in vitro and in vivo.\",\n      \"method\": \"X-ray crystallography of ARM–VMN complex, genetic Sarm1 knockout, in vitro neuron protection assay, in vivo mouse model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with in vitro and in vivo functional validation\",\n      \"pmids\": [\"34870595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nicotinic acid mononucleotide (NaMN) is an allosteric SARM1 inhibitor that competes with NMN for binding to the SARM1 ARM domain allosteric pocket and promotes the open, autoinhibited ARM conformation. Co-crystal structure of NaMN with the ARM domain shows direct binding to the allosteric site, and NaMN-mediated SARM1 inhibition contributes to long-term axon protection.\",\n      \"method\": \"X-ray crystallography (ARM–NaMN complex), in vitro NADase competition assay, mutagenesis, neuronal axon protection assay\",\n      \"journal\": \"Experimental Neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical competition assay and mutagenesis in one study\",\n      \"pmids\": [\"34403688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tryptoline acrylamide compounds site-specifically and stereoselectively modify cysteine-311 (C311) in the non-catalytic ARM domain of SARM1, allosterically inhibiting NADase activity. C311A/C311S mutants are resistant to inhibition. These covalent inhibitors stereoselectively block vincristine- and vacor-induced neurite degeneration in primary DRG neurons.\",\n      \"method\": \"Chemical proteomics (activity-based protein profiling), site-directed mutagenesis, in vitro NADase assay, primary neuron degeneration assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical proteomic site identification + mutagenesis abolishing inhibition + cellular functional assay, multiple orthogonal methods\",\n      \"pmids\": [\"35994671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C. elegans TIR-1/SARM1 undergoes a phase transition (oligomerization into visible puncta) upon physiological stress, and this multimerization dramatically potentiates its NAD+ glycohydrolase activity in vitro. Genetic mutations blocking either multimerization or NADase activity prevent p38/PMK-1 immune pathway activation and increase susceptibility to bacterial infection, placing TIR-1 NADase activity downstream of oligomerization and upstream of p38 MAPK.\",\n      \"method\": \"Fluorescence imaging of TIR-1–GFP puncta, in vitro enzyme kinetics, C. elegans genetics (loss-of-function mutants, epistasis), p38 phosphorylation assay, infection survival assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of phase-transition-dependent NADase, genetic epistasis, multiple orthogonal methods; C. elegans ortholog of SARM1\",\n      \"pmids\": [\"35098926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ULK1 (autophagy kinase) physically interacts with SARM1 via SARM1 SAM domains, and this interaction increases upon neurite damage. ULK1 inhibition or Ulk1 knockdown attenuates SARM1 puncta accumulation in neurites and reduces neurite fragmentation. In vivo, axonal ULK1 activation and SARM1 accumulation are both reduced in Beclin1 autophagy hypomorph mice after SCI.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), domain-deletion analysis (SAM domains), ULK1 inhibitor and siRNA knockdown, immunofluorescence, spinal cord injury mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping plus functional knockdown, single lab, in vivo corroboration\",\n      \"pmids\": [\"36375051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C. elegans and mammalian neurons, TIR-1/SARM1 cell-autonomously inhibits axon regeneration by activating the NSY-1/ASK1 MAPK cascade, independently of its NADase activity and degeneration-promoting function. Simultaneously, TIR-1 promotes axon degeneration on the other side of the injury via the DLK-1 MAPK cascade. Human SARM1 also inhibits axon regeneration cell-intrinsically.\",\n      \"method\": \"C. elegans tir-1 mutants (loss-of-function), NADase-deficient SARM1 variants, epistasis with NSY-1/ASK1 and DLK-1 pathway mutants, human SARM1 expression in C. elegans, axon regeneration imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with NADase-null separation-of-function allele, multiple MAPK pathway mutants, conserved in human SARM1\",\n      \"pmids\": [\"37083456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARM1-dependent NAD+ hydrolysis is required for Drosophila neuromuscular junction (NMJ) development: NMJ overgrowth scales with the amount of SARM1 NADase activity, and degenerative and developmental SARM1 signaling use distinct upstream and downstream mechanisms despite sharing the NADase requirement.\",\n      \"method\": \"Transgenic Drosophila with graded NADase-activity SARM1 variants, NMJ morphometry, genetic epistasis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — activity-graded transgenic series in Drosophila, single lab, separation-of-function analysis\",\n      \"pmids\": [\"35737728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SARM inhibits MAPK activation (both TRIF- and MyD88-mediated, and basal) leading to suppression of AP-1, in addition to NF-κB and IRF3. RNAi knockdown of SARM elevates basal AP-1 activity. Truncated SARM changes subcellular localization, indicating that the N-terminal and SAM domains regulate SARM subcellular distribution and activity.\",\n      \"method\": \"Overexpression and RNAi knockdown, MAPK phosphorylation assay, AP-1 reporter assay, subcellular fractionation/localization\",\n      \"journal\": \"European Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple pathway assays with RNAi, single lab, localization experiment with truncation mutants\",\n      \"pmids\": [\"20306472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The BB-loop residue G601 in the SARM TIR domain is essential for SARM's interaction with both MyD88 and TRIF; a G601A mutant loses the ability to suppress LPS-induced IL-8 and TNF-α. A short peptide derived from the BB-loop motif also interacts with MyD88 in vitro, demonstrating that the BB loop mediates SARM–adaptor TIR–TIR interactions.\",\n      \"method\": \"Recombinant TIR domain interaction assays (in vitro), site-directed mutagenesis (G601A), cytokine reporter assays in HEK293 cells\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — purified protein interaction + mutagenesis + cellular functional assay, single lab\",\n      \"pmids\": [\"26592460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SARM is required for CCL5 production in macrophages across multiple pattern-recognition pathways (TLR and cytosolic RNA/DNA sensing). SARM acts at the level of the Ccl5 promoter, being critical for recruitment of transcription factors and RNA polymerase II, without affecting MAPK or NF-κB/IRF activation, mRNA stability, or splicing.\",\n      \"method\": \"Sarm1-/- macrophages, ELISA, chromatin immunoprecipitation (transcription factor and Pol II at Ccl5 promoter), RT-PCR, cytokine profiling\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP mechanistic evidence plus genetic KO, single lab, novel transcriptional role\",\n      \"pmids\": [\"24711619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NLRX1 associates with SARM1 at the mitochondrial matrix in non-neuronal cells; in these cells, the apoptotic role of NLRX1 is fully dependent on SARM1, placing SARM1 downstream of NLRX1 in apoptosis regulation. Wallerian degeneration in primary neurons occurs in a SARM1-dependent but NLRX1-independent manner, indicating that different SARM1 subcellular pools mediate distinct functions.\",\n      \"method\": \"Co-immunoprecipitation (endogenous NLRX1–SARM1), mitochondrial fractionation, siRNA knockdown, Sarm1-/- neurons, cell-death assay\",\n      \"journal\": \"Molecular and Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — endogenous co-IP with functional knockdown, single lab, fractionation supports localization\",\n      \"pmids\": [\"30191480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UXT isoforms differentially regulate SARM-induced apoptosis: UXT V1 reduces caspase-8 activity (anti-apoptotic), while UXT V2 strongly increases caspase-8 and enhances SARM-induced apoptosis via the extrinsic pathway and mitochondrial depolarization. Both isoforms interact with SARM by yeast two-hybrid analysis.\",\n      \"method\": \"Yeast two-hybrid (UXT–SARM interaction), overexpression, caspase-8 activity assay, mitochondrial depolarization measurement\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid interaction plus overexpression assays, single lab, no endogenous co-IP\",\n      \"pmids\": [\"24021647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A nanobody (Nb-C6) specifically recognizes NMN-activated SARM1. Cryo-EM of the NMN/SARM1/Nb-C6 complex reveals an octameric structure in which ARM domains bend significantly inward and swing outward together with TIR domains upon activation. Nb-C6 binds the SAM domain of activated SARM1. Mass spectrometry indicates that activated SARM1 in solution is highly dynamic, with neighboring TIRs forming transient dimers via the BB-loop surface.\",\n      \"method\": \"Nanobody generation, cryo-EM of activated SARM1 complex, native mass spectrometry, hydrogen–deuterium exchange MS\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of activated state plus native MS dynamics, orthogonal structural methods\",\n      \"pmids\": [\"36550129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Acidic pH (protonation of negative residues) activates SARM1 enzymatic activity even more efficiently than NMN. Mutagenesis revealed: E689Q in TIR constitutively activates SARM1 by disrupting a salt bridge with R216 in ARM that maintains autoinhibition; K597E inhibits activation; H685A eliminates catalytic activity. Distinct classes of chemical inhibitors act either by blocking activation (NAD, dHNN, disulfiram) or by inhibiting catalysis (nicotinamide, Tweens).\",\n      \"method\": \"In vitro NADase assay at varying pH, systematic site-directed mutagenesis, inhibitor classification\",\n      \"journal\": \"The FEBS Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with systematic mutagenesis, single lab\",\n      \"pmids\": [\"34213829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cysteines 629 and 635 in the SARM1 TIR domain are critical for SARM1 catalysis; site-directed mutagenesis of these residues abolishes or reduces NADase activity. Zinc chloride inhibits SARM1 in a noncompetitive manner, suggesting an allosteric binding pocket on SARM1.\",\n      \"method\": \"High-throughput NADase screen, noncompetitive inhibition kinetics, site-directed mutagenesis (C629 and C635)\",\n      \"journal\": \"Bioorganic & Medicinal Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis identifying catalytic cysteines, single lab\",\n      \"pmids\": [\"32828421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C. elegans, CaMKII/UNC-43 activates the conserved Sarm1/TIR-1–ASK1/NSY-1–p38 MAPK pathway to protect against axon degeneration caused by loss of mitochondria. Disruption of a trafficking complex (calsyntenin/CASY-1, Mint/LIN-10, kinesin) activates this CaMKII–Sarm1–MAPK neuroprotective pathway through L-type voltage-gated calcium channels.\",\n      \"method\": \"Unbiased genetic screen, C. elegans genetics (loss-of-function and epistasis), in vivo axon imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genetic screen plus epistasis in C. elegans, single lab; SARM1 ortholog context\",\n      \"pmids\": [\"35285800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRPV1 interacts with SARM1 via TRPV1's N-terminal ankyrin repeat domain binding to the TIR-His583 domain of SARM1. This interaction, confirmed by co-IP, SPR, BRET, and NanoBiT, is required for TRPV1 to maintain hepatic stellate cell quiescence and prevent NF-κB-dependent pro-inflammatory activation and liver fibrosis.\",\n      \"method\": \"Mass spectrometry (interactome), co-immunoprecipitation, surface plasmon resonance, BRET, NanoBiT bioluminescence proximity assay, domain-mapping, Trpv1-/- mice\",\n      \"journal\": \"Journal of Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (SPR, BRET, NanoBiT, co-IP) plus in vivo KO, single lab\",\n      \"pmids\": [\"36669703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human SARM1 regulates proinflammatory cytokines in monocytes through both NADase-dependent and NADase-independent mechanisms: TNF mRNA induction is negatively regulated independently of NADase activity, while IL-1β secretion is inhibited via NADase-dependent suppression of pro-IL-1β expression AND via NADase-independent suppression of NLRP3 inflammasome processing.\",\n      \"method\": \"SARM1 knockout human monocytes, NADase-inactive SARM1 mutant, TLR4 stimulation, ELISA, RT-PCR, NLRP3 inflammasome assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus separation-of-function NADase mutant in human cells, single lab, multiple readouts\",\n      \"pmids\": [\"38832024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SAG-dependent ubiquitin-proteasome system (UPS) targets SARM1 for ubiquitination and proteasomal degradation in hepatocellular carcinoma; upregulated SAG promotes high-molecular-weight ubiquitination of SARM1 (and Noxa), reducing their levels. SARM1 overexpression activates caspase-3 and caspase-9, reducing HCC cell viability.\",\n      \"method\": \"Co-IP of ubiquitinated SARM1, SAG overexpression/knockdown, caspase activation assay, HCC tissue immunohistochemistry\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP ubiquitination without reconstituted E3 assay, correlative tissue data\",\n      \"pmids\": [\"27551463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In a rat CMT2A model (Mfn2H361Y), deletion of Sarm1 rescues axonal, synaptic, muscle, and functional phenotypes, and also suppresses mitochondrial defects (number, size, cristae density) caused by the MFN2 mutation, revealing a positive feedback loop in which dysfunctional mitochondria activate SARM1 and activated SARM1 feeds back to exacerbate mitochondrial pathology.\",\n      \"method\": \"Sarm1-/- × Mfn2H361Y double-mutant rat model, neuromuscular junction histology, electron microscopy (mitochondria), behavioral testing\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double-mutant rat model with multiple orthogonal phenotypic readouts; feedback loop established by genetic rescue\",\n      \"pmids\": [\"36287202\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SARM1 is an NAD+-cleaving enzyme (NADase) whose activity resides in its TIR domain and is normally held in check by an autoinhibited homo-octameric structure in which NAD+ bound to the N-terminal ARM domain locks the TIR domains apart; axon injury or disease increases the NMN/NAD+ ratio, causing NMN to displace NAD+ from the ARM allosteric site, relieving autoinhibition and allowing TIR dimerization, catastrophic NAD+ depletion, ATP loss, calcium influx, and programmed axon self-destruction (Wallerian degeneration), while in innate immune cells SARM1 negatively regulates TLR/TRIF signaling, suppresses NLRP3 inflammasome-dependent IL-1β and pyroptosis, and modulates macrophage NAD+ metabolism through both NADase-dependent and -independent mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SARM1 is an injury-activated NAD+-cleaving enzyme that functions as the central executioner of programmed axon self-destruction (Wallerian degeneration) and additionally serves as a regulator of innate immune signaling [#3, #0]. The protein assembles into an autoinhibited homo-octameric ring built from SAM-domain 'lock and key' interfaces, with the catalytic TIR domains held isolated and inactive by NAD+ bound at an allosteric site in the N-terminal ARM domain and by multiple intramolecular ARM\\u2013TIR locks [#4, #5, #7, #9]. Axon injury raises the NMN/NAD+ ratio; NMN competes with NAD+ at the ARM allosteric pocket, breaks the ARM\\u2013TIR lock, and triggers the conformational change that frees the TIR domains to dimerize and consume NAD+ catastrophically [#6, #8, #30]. The NADase activity, which resides in the TIR domain and depends on conserved catalytic residues, is essential for degeneration: forced TIR dimerization causes NAD+ loss and neuronal death, and NADase-dead or dominant-negative constructs protect axons in vitro and in vivo [#2, #3, #32]. Downstream, SARM1 NADase activity initiates an ordered collapse \\u2014 ATP loss, mitochondrial depolarization, calcium influx, phosphatidylserine externalization, and membrane rupture [#17, #11]. SARM1 acts genetically downstream of loss of the axon survival factor NMNAT2, and diverse insults including mitochondrial depolarization, TNF-driven noncanonical necroptosis (via MLKL-dependent NMNAT2/STMN2 loss), and the neurotoxin vacor converge on this NMN/NAD+-sensing switch [#10, #11, #15, #18]. The pathway is pharmacologically tractable: NaMN is an endogenous allosteric inhibitor, and covalent ligands targeting ARM cysteine C311 block degeneration [#19, #20]. Genetic deletion of Sarm1 rescues axonal, synaptic, and mitochondrial pathology in a CMT2A (Mfn2) model, defining a feedback loop between mitochondrial dysfunction and SARM1 activation [#37]. Separately, SARM1 negatively regulates TRIF-dependent TLR signaling and restrains the NLRP3 inflammasome to suppress IL-1\\u03b2 and pyroptosis through both NADase-dependent and NADase-independent mechanisms [#0, #14, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first molecular function of SARM1, identifying it as a negative regulator that physically engages the TLR adaptor TRIF, defining a role outside the nervous system.\",\n      \"evidence\": \"Co-IP of SARM\\u2013TRIF and RNAi knockdown with cytokine reporters in human cells\",\n      \"pmids\": [\"16964262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of TRIF binding\", \"Did not address any neuronal function\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined SARM1 as a pro-degenerative factor and mapped the SAM domains to oligomerization and the TIR domain to engagement of a destruction pathway, framing the modular logic of the protein.\",\n      \"evidence\": \"RNAi screen in DRG neurons with domain-deletion/point mutants, co-IP, genetic KO, and dominant-negative overexpression\",\n      \"pmids\": [\"23946415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic identity of the TIR domain not yet known\", \"Activating signal upstream not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SARM1 downstream of ROS and mitochondrial depolarization in a distinct neuronal death program, ordering it within the degeneration cascade.\",\n      \"evidence\": \"CCCP depolarization with Sarm1-null neurons, ROS/ATP/calcium readouts\",\n      \"pmids\": [\"25009267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor linking depolarization to SARM1 not identified\", \"Catalytic mechanism still unknown at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established genetic epistasis showing SARM1 acts downstream of NMNAT2 loss, linking axon survival-factor turnover to a SARM1-dependent destruction pathway.\",\n      \"evidence\": \"Double Sarm1/Nmnat2 knockout mice with NAMPT inhibition and metabolite measurement\",\n      \"pmids\": [\"25818290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish NMN as the direct activating ligand\", \"Mechanism connecting NMNAT2 loss to SARM1 activity not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the TIR domain as the source of NAD+-consuming activity unique among TIR adaptors and conserved to C. elegans, recasting SARM1 as an enzyme rather than a scaffold.\",\n      \"evidence\": \"Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, N-terminus\\u2013TIR co-IP, C. elegans genetics\",\n      \"pmids\": [\"27671644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly measure purified-enzyme NADase kinetics\", \"Structural basis of autoinhibition not yet solved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Directly demonstrated injury-activated intrinsic NADase activity is essential for degeneration and that blocking it is axon-protective in vivo, validating SARM1 as a therapeutic target.\",\n      \"evidence\": \"In vitro NADase assay, AAV delivery of dominant-negative constructs, nerve transection, KO comparison\",\n      \"pmids\": [\"30642945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the allosteric activation mechanism\", \"Octameric architecture not yet defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Solved the octameric ring architecture and mapped SAM\\u2013SAM interfaces, providing the structural unit of SARM1 assembly.\",\n      \"evidence\": \"Crystal structure of SAM1-2, EM of full-length protein, SEC, mutagenesis, cell-death assay\",\n      \"pmids\": [\"31278906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the autoinhibitory ARM\\u2013TIR contacts\", \"Did not define the activating ligand\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Converging cryo-EM studies established that NAD+ binding to the ARM domain enforces an autoinhibited octamer that locks TIR domains apart, with NMN acting as an endogenous activator that disrupts the ARM\\u2013TIR lock.\",\n      \"evidence\": \"Multiple cryo-EM structures of autoinhibited and active states, NADase assays, product-inhibition, and interface mutagenesis (Nature, Cell Reports, eLife)\",\n      \"pmids\": [\"33053563\", \"32755591\", \"33185189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution NMN-bound activated catalytic site not fully resolved\", \"Dynamics of TIR dimerization during catalysis incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified cADPR as an in vivo product of SARM1 NAD+ cleavage and a quantitative biomarker, while showing it is not the effector of degeneration.\",\n      \"evidence\": \"Mass spectrometry, Sarm1 gene-dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes\",\n      \"pmids\": [\"32087251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The metabolic consequence driving degeneration (vs cADPR) not isolated here\", \"Basal physiological role of constitutive activity unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the NMN/NAD+ ratio as the activating signal through competitive ARM-domain binding, unifying the metabolic trigger with the structural switch.\",\n      \"evidence\": \"Cryo-EM/crystallography of ARM\\u2013NMN, biophysical binding, NADase assays, mutagenesis, cellular degeneration; plus mapping of five autoinhibitory interfaces\",\n      \"pmids\": [\"33657413\", \"33468661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dynamics of NMN/NAD+ sensing during injury not directly imaged\", \"How multiple interfaces release sequentially not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the temporal order of downstream destruction events at single-axon resolution, placing NADase activity at the apex of an ATP\\u2192mitochondrial\\u2192calcium\\u2192membrane cascade.\",\n      \"evidence\": \"Live imaging of single sensory axons with genetically encoded ATP/calcium/PS sensors and KO controls\",\n      \"pmids\": [\"34779400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from NAD+ loss to calcium influx not pinned to specific channels\", \"PS-externalization machinery not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the activator/inhibitor pharmacology by structurally defining the potent activator VMN and the endogenous inhibitor NaMN at the ARM allosteric pocket, plus pH and salt-bridge determinants of activation.\",\n      \"evidence\": \"Crystal structures of ARM\\u2013VMN and ARM\\u2013NaMN, NADase competition assays, mutagenesis (E689/R216 salt bridge), neuron protection\",\n      \"pmids\": [\"34870595\", \"34403688\", \"34213829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NaMN-based therapeutic window in vivo not established here\", \"Physiological relevance of pH activation not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified druggable allosteric and catalytic sites (covalent C311 ligands, catalytic cysteines, zinc) enabling small-molecule inhibition of degeneration.\",\n      \"evidence\": \"Chemical proteomics with C311 mutagenesis and DRG degeneration assays; high-throughput NADase screen with C629/C635 mutagenesis\",\n      \"pmids\": [\"35994671\", \"32828421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and selectivity of covalent inhibitors not fully established\", \"Relationship between catalytic cysteines and the NAD+ catalytic mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Captured the activated, conformationally dynamic state by cryo-EM and native MS, showing ARM inward bending and transient BB-loop-mediated TIR dimers as the catalytic species.\",\n      \"evidence\": \"Activation-state-specific nanobody, cryo-EM of NMN/SARM1/Nb-C6, native MS and HDX-MS\",\n      \"pmids\": [\"36550129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the catalytically competent TIR dimer not solved\", \"Whether the octamer disassembles or remains intact during catalysis debated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SARM1 activation drives disease in a CMT2A mitochondrial-mutation model, with Sarm1 deletion rescuing both axonal and mitochondrial pathology, establishing a degenerative feedback loop.\",\n      \"evidence\": \"Sarm1-/- \\u00d7 Mfn2H361Y double-mutant rat model with NMJ histology, EM, and behavior\",\n      \"pmids\": [\"36287202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular signal from mutant mitochondria to SARM1\", \"Generalizability to other CMT subtypes not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that SARM1 NADase activity also drives non-degenerative developmental and immune phenotypes (Drosophila NMJ growth; C. elegans p38/PMK-1 innate immunity via stress-induced phase transition), distinguishing degenerative from physiological signaling.\",\n      \"evidence\": \"Graded-NADase transgenic Drosophila and C. elegans TIR-1 imaging/enzymology with infection assays\",\n      \"pmids\": [\"35737728\", \"35098926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian SARM1 supports analogous developmental NADase signaling not shown\", \"Effectors linking NADase output to p38/MAPK not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved a NADase-independent arm of SARM1 function in axon regeneration via MAPK cascades, separating its scaffolding/signaling roles from its enzymatic destruction role.\",\n      \"evidence\": \"C. elegans tir-1 mutants and NADase-deficient SARM1 with NSY-1/ASK1 and DLK-1 epistasis, human SARM1 in worms\",\n      \"pmids\": [\"37083456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian regeneration role of SARM1 not fully mapped\", \"Molecular partners coupling SARM1 to ASK1/DLK1 not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected the dual NADase-dependent and -independent immune functions in human cells, showing TNF and IL-1\\u03b2 are controlled through distinct enzymatic and non-enzymatic routes.\",\n      \"evidence\": \"SARM1-KO human monocytes with NADase-inactive mutant, TLR4 stimulation, ELISA/RT-PCR, NLRP3 assay\",\n      \"pmids\": [\"38832024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets of the NADase-independent suppression not identified\", \"Single-lab finding in monocytes; in vivo relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same NMN/NAD+-sensing enzyme is wired to opposing outcomes \\u2014 axon destruction, axon regeneration inhibition, developmental NMJ growth, and immune regulation \\u2014 across cell types and subcellular pools remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular pools (mitochondrial vs cytosolic) directing distinct functions not fully mapped\", \"The effectors translating NAD+ loss into calcium influx and membrane breakdown are unidentified\", \"How non-enzymatic SARM1 signaling engages MAPK and immune pathways mechanistically is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 3, 5, 16, 32]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 8, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 11, 12, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 13, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 8, 16, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 14, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 25, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [23, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [37, 18]}\n    ],\n    \"complexes\": [\n      \"SARM1 homo-octamer\",\n      \"SARM1\\u2013PINK1\\u2013TRAF6 mitochondrial complex\"\n    ],\n    \"partners\": [\n      \"TRIF\",\n      \"PINK1\",\n      \"TRAF6\",\n      \"NLRX1\",\n      \"ULK1\",\n      \"TRPV1\",\n      \"MyD88\",\n      \"UXT\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}