Affinage

SARM1

NAD(+) hydrolase SARM1 · UniProt Q6SZW1

Length
724 aa
Mass
79.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SARM1 is a homo-octameric NAD+ glycohydrolase that serves as the central executioner of programmed axon degeneration (Wallerian degeneration) and additionally functions as a negative regulator of innate immune signaling. In healthy axons, NAD+ binds an allosteric pocket in the N-terminal ARM domain, locking the catalytic TIR domains in an inactive conformation within the octameric ring; upon axonal injury, loss of the labile enzyme NMNAT2 causes NMN to accumulate and competitively displace NAD+ from the ARM pocket, triggering a conformational change that liberates TIR domains to dimerize and cleave NAD+ into ADPR, cADPR, and nicotinamide, initiating an ordered cascade of ATP depletion, mitochondrial depolarization, calcium influx, and membrane destruction (PMID:28334607, PMID:33053563, PMID:33657413, PMID:34779400, PMID:25818290). SARM1 also regulates axon regeneration through a NADase-independent activation of the ASK1 MAPK cascade, and phase-transition-driven multimerization of its TIR domain potentiates both its enzymatic activity and p38-dependent innate immune signaling in C. elegans epithelial cells (PMID:37083456, PMID:35098926). In the mammalian immune system, SARM1 negatively regulates TRIF-dependent TLR signaling, promotes CCL5 transcription in macrophages, and suppresses NLRP3 inflammasome-mediated IL-1β processing in monocytes through both NADase-dependent and NADase-independent mechanisms (PMID:16964262, PMID:24711619, PMID:38832024).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    The first mammalian function assigned to SARM1 established it as a negative regulator of TRIF-dependent TLR signaling, distinguishing it from all other TIR-domain adaptors that positively transduce TLR signals.

    Evidence Co-immunoprecipitation of SARM with TRIF and RNAi knockdown with cytokine readout in human cells

    PMID:16964262

    Open questions at the time
    • Mechanism by which SARM1 inhibits TRIF signaling (direct competition vs. scaffolding) not resolved
    • Whether this immune function requires NADase activity was unknown
  2. 2012 Medium

    SARM1 was shown to localize to mitochondria and promote intrinsic apoptosis in T cells via ROS generation and mitochondrial depolarization, revealing a cell-death-promoting role beyond TLR signaling.

    Evidence SARM knockdown in T cells; domain-deletion constructs; Bcl-xL overexpression and Bax/Bak double-KO rescue

    PMID:23175186

    Open questions at the time
    • Physiological trigger for SARM1-mediated T cell apoptosis unclear
    • Whether the T cell apoptotic mechanism is distinct from the axon degeneration mechanism was unresolved
  3. 2013 High

    Domain dissection established that SAM-domain-mediated multimerization and TIR-domain activity are both essential for axon degeneration, and identified ARM-TIR autoinhibition, providing the first mechanistic framework for SARM1 activation.

    Evidence Domain-deletion and point-mutant analysis, co-IP, subcellular fractionation in DRG neurons

    PMID:23946415

    Open questions at the time
    • Nature of the autoinhibitory interaction (direct binding site) not defined at atomic resolution
    • Whether SARM1 multimerization state is fixed or injury-regulated was unknown
  4. 2015 High

    Genetic epistasis in double-knockout mice placed SARM1 downstream of NMNAT2 loss, establishing the NMNAT2→SARM1 axis as the core pathway of Wallerian degeneration and implicating NMN accumulation as a potential trigger.

    Evidence SARM1 KO × NMNAT2 KO double-mutant mice; NAMPT inhibitor pharmacology

    PMID:25818290

    Open questions at the time
    • Whether NMN directly activates SARM1 or acts indirectly was unknown
    • Molecular identity of the SARM1-activating signal not established
  5. 2016 High

    Identification of TIR-domain dimerization as the trigger for NAD+ consumption, and mapping of a SARM1-specific SS loop required for enzymatic activity, refined the activation mechanism to the level of specific TIR structural elements.

    Evidence TIR dimerization constructs; SS-loop and BB-loop mutagenesis; NAD+ measurement in neurons

    PMID:27671644

    Open questions at the time
    • The enzymatic activity of the TIR domain was inferred but not directly reconstituted as NADase at this point
  6. 2017 High

    The landmark discovery that the SARM1 TIR domain is an intrinsic NADase — cleaving NAD+ into ADPR, cADPR, and nicotinamide — transformed understanding from a signaling adaptor to a metabolic enzyme and explained how SARM1 depletes axonal NAD+.

    Evidence In vitro NADase assay with purified proteins from multiple expression systems; mutagenesis in traumatic and vincristine neuronal injury models

    PMID:28334607

    Open questions at the time
    • How the NADase is kept inactive in healthy axons at the structural level was not yet resolved
    • The allosteric regulation mechanism was unknown
  7. 2019 High

    Crystal structure of the SAM1-2 tandem domains revealed an octameric ring architecture, establishing the stoichiometry of the SARM1 complex and showing that SAM-mediated oligomerization is essential for degenerative function.

    Evidence Crystal structure of SAM1-2 octameric ring; size-exclusion chromatography and EM of full-length SARM1; SAM interface mutagenesis with cell death assays

    PMID:31278906

    Open questions at the time
    • Full-length octamer structure at high resolution not yet available
    • How the ARM and TIR domains are arranged within the octamer was unknown
  8. 2020 High

    Multiple independent cryo-EM structures revealed the full autoinhibition mechanism: NAD+ binds an allosteric pocket in the ARM domain distinct from the catalytic site, locking TIR domains apart within the compact octamer; loss of allosteric NAD+ binding constitutively activates SARM1.

    Evidence Cryo-EM structures at 2.7–3.3 Å from three independent groups; allosteric site mutagenesis; NADase and axon degeneration assays

    PMID:32755591 PMID:33053563 PMID:33185189

    Open questions at the time
    • How NMN displaces NAD+ from the allosteric site was structurally unresolved
    • Transition state between autoinhibited and active conformations not captured at high resolution
  9. 2020 High

    Live single-axon imaging defined the ordered downstream cascade of SARM1 activation — ATP loss → mitochondrial failure → calcium influx → phosphatidylserine exposure → membrane rupture — establishing the complete execution sequence of axon self-destruction.

    Evidence Fluorescent reporters for ATP, mitochondria, calcium, phosphatidylserine, and membrane integrity in primary mouse neurons

    PMID:34779400

    Open questions at the time
    • Molecular executioners acting between SARM1-driven NAD+ loss and calcium influx not identified
    • Whether any step is independently reversible is unknown
  10. 2020 High

    Mitochondrial dysfunction and TNF-α/necroptotic signaling were both shown to converge on SARM1 via NMNAT2 depletion, generalizing the activation mechanism beyond traumatic injury to neuroinflammatory and metabolic contexts.

    Evidence Pharmacological mitochondrial uncoupling and SARM1/MLKL KO epistasis in mouse neurons and Drosophila; NMNAT2 protein measurement

    PMID:31740269 PMID:32609299

    Open questions at the time
    • Whether SARM1 is activated in human neurodegenerative disease in vivo remains to be demonstrated with direct patient tissue evidence
  11. 2021 High

    Cryo-EM and crystal structures of the ARM domain bound to NMN showed that NMN competitively displaces NAD+ from the allosteric pocket, completing the metabolic sensor model: a rising NMN/NAD+ ratio is the proximate activation signal.

    Evidence Cryo-EM of SARM1 ARM-NMN complex; binding assays; NMN-site mutagenesis; cellular axon degeneration assays

    PMID:33657413

    Open questions at the time
    • Quantitative in vivo NMN/NAD+ threshold for activation not established
    • Whether other pyridine nucleotides modulate the switch under physiological conditions is incompletely explored
  12. 2021 High

    The toxicant metabolite VMN and the endogenous metabolite NaMN were shown to activate and inhibit SARM1, respectively, by binding the same ARM allosteric pocket, demonstrating that this site integrates diverse metabolic signals and is a druggable target.

    Evidence Crystal structures of ARM domain with VMN and NaMN; NADase activity assays; SARM1-KO rescue from vacor toxicity in vitro and in vivo

    PMID:34403688 PMID:34870595

    Open questions at the time
    • Whether NaMN levels change sufficiently during injury to be physiologically relevant is untested
    • Pharmacokinetic properties of ARM-targeting inhibitors in vivo are undeveloped
  13. 2021 High

    Citrate-induced phase transition of SARM1 TIR domains was shown to enhance NADase activity ~2000-fold and to be required for axon degeneration in C. elegans, revealing higher-order multimerization as an additional regulatory layer beyond octamer formation.

    Evidence In vitro NADase kinetics with citrate; G601P mutagenesis; cell puncta imaging; C. elegans axon degeneration

    PMID:34184985

    Open questions at the time
    • Whether citrate-induced phase transition occurs in mammalian axons is unconfirmed
    • Structural basis of the phase-transitioned state is unknown
  14. 2022 High

    SARM1 was found to inhibit axon regeneration through a NADase-independent ASK1-MAPK pathway, revealing a dual role where SARM1 promotes degeneration and suppresses regeneration via distinct downstream effectors.

    Evidence C. elegans tir-1 mutant genetic epistasis with ask1 and dlk-1 MAPK mutants; NADase-dead mutants; human SARM1 cross-species rescue

    PMID:37083456

    Open questions at the time
    • Whether the regeneration-inhibitory function is conserved in mammalian injury models in vivo is not established
    • The direct substrate or binding partner in the ASK1 activation step is unidentified
  15. 2022 High

    Cysteine-311 in the ARM domain was identified as a covalent druggable site: electrophilic inhibitors targeting C311 block NMN-induced SARM1 activation and prevent chemotoxic axon degeneration, establishing a pharmacological strategy.

    Evidence Chemical proteomics; C311A/C311S mutagenesis; vincristine and vacor neurite degeneration assays

    PMID:35994671

    Open questions at the time
    • In vivo efficacy and selectivity of C311-targeting compounds not demonstrated
    • Whether C311 modification affects allosteric NAD+ binding or a distinct mechanism is not structurally resolved
  16. 2024 Medium

    SARM1 was shown to suppress TLR4-driven TNF induction and NLRP3 inflammasome-mediated IL-1β processing in human monocytes through separable NADase-dependent and NADase-independent mechanisms, resolving the long-standing question of whether immune functions require enzymatic activity.

    Evidence SARM1 knockdown in human monocytes; NADase-dead mutant; TNF/IL-1β mRNA and protein measurement; NLRP3 activity assay

    PMID:38832024

    Open questions at the time
    • Molecular target of the NADase-independent immune suppression not identified
    • Whether SARM1 NADase activity modulates immune outcomes in vivo is untested
    • Single-lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the molecular executioners acting between SARM1-driven NAD+ depletion and axon membrane rupture, the quantitative NMN/NAD+ threshold for activation in vivo, whether SARM1 phase transitions occur in mammalian neurons, and whether pharmacological SARM1 inhibition can protect axons in human neurodegenerative disease.
  • Downstream effectors between NAD+ loss and calcium influx remain unidentified
  • In vivo NMN/NAD+ activation threshold not quantified
  • No clinical evidence for SARM1 inhibitor efficacy in neurodegeneration

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 7 GO:0140299 molecular sensor activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 7 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
NLRX1NMNAT2PINK1TRAF6TRIFTRPV1ULK1
Complex memberships
SARM1 homo-octamer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 The SARM1 TIR domain possesses intrinsic NAD+ cleavage (NADase) activity, cleaving NAD+ into ADP-ribose (ADPR), cyclic ADPR (cADPR), and nicotinamide; nicotinamide serves as a feedback inhibitor. This NADase activity is required in axons to promote NAD+ depletion and axonal degeneration after injury. In vitro NADase assay with purified proteins from mammalian cells, bacteria, and cell-free translation system; mutagenesis of full-length SARM1 in traumatic and vincristine-induced neuronal injury models Neuron High 28334607
2006 Human SARM is a negative regulator of TRIF-dependent TLR signaling; it associates with TRIF and blocks gene induction downstream of TRIF but not MyD88. Knockdown of endogenous SARM enhances TRIF-dependent cytokine and chemokine induction. Co-immunoprecipitation (SARM-TRIF association), RNAi knockdown with cytokine/chemokine readout, overexpression epistasis Nature immunology High 16964262
2013 SARM1-mediated axon degeneration requires both SAM-domain-mediated SARM1 homodimerization/multimerization and TIR-domain activity. SAM domains are necessary and sufficient for SARM-SARM binding; deletion of either SAM or TIR abolishes pro-degenerative activity; SARM mutants lacking TIR act as dominant negatives. SARM1 associates with neuronal mitochondria via its N-terminal sequence, but mitochondrial localization is not required for axon degeneration. RNAi screen in DRG neurons; domain-deletion and point-mutant analysis; protein-protein interaction studies (co-IP); mitochondrial localization by subcellular fractionation and imaging The Journal of neuroscience High 23946415
2021 SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio. NMN and NAD+ compete for binding to the autoinhibitory N-terminal ARM domain of SARM1; NMN binding promotes a conformational change that activates the TIR-domain NADase. NMN binding is required for injury-induced SARM1 activation and axon destruction. Cryo-EM structures of SARM1 ARM domain bound to NMN and of homo-octameric SARM1; biochemical binding assays; mutagenesis of NMN-binding residues; cellular axon degeneration assays Neuron High 33657413
2020 NAD+ is an endogenous ligand of the SARM1 ARM domain; its binding mediates self-inhibition of the TIR-domain NADase through the ARM-TIR domain interface. Disruption of the NAD+-binding site or ARM-TIR interaction causes constitutive SARM1 activation and axonal degeneration. Cryo-EM structures of full-length SARM1; mutagenesis of NAD+-binding site and domain interface; neuronal axon degeneration assays Nature High 33053563
2020 Cryo-EM structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) reveal an octameric core; autoinhibition involves a lock between the ARM domain and TIR domain. Mutations breaking this lock activate SARM1. Active SARM1 is product-inhibited by nicotinamide (NAM) and cannot be further activated by NMN. Cryo-EM; mutagenesis; cellular death assays Cell reports High 32755591
2020 Cryo-EM maps of SARM1 at 2.9 and 2.7 Å show a packed homo-octameric conformation stabilized by allosteric NAD+ binding away from the catalytic sites, preventing TIR dimerization and activation. Mutation of the allosteric NAD+-binding site yields constitutively active SARM1. Cryo-EM; allosteric site mutagenesis; NADase activity assays eLife High 33185189
2016 Dimerization of the SARM1 TIR domain promotes NAD+ consumption and neuronal destruction. A SARM1-specific 'SS loop' in the TIR domain is required for NAD+ loss and axon degeneration. The SARM1 BB-loop residue is dispensable for TIR enzymatic activity but required for injury-induced activation of full-length SARM1. A physical interaction exists between the autoinhibitory N-terminus and the TIR domain, mediating autoinhibition. TIR domain dimerization constructs; mutagenesis of TIR motifs; NAD+ measurement; axon degeneration assays; co-IP of N-terminus with TIR domain Proceedings of the National Academy of Sciences of the United States of America High 27671644
2021 Multiple intramolecular and intermolecular domain interfaces are required for SARM1 autoinhibition: ARM-SAM (intramolecular and intermolecular), ARM-ARM (intermolecular), and two ARM-TIR interfaces (each formed between one TIR and two distinct ARM domains). Each interface is non-redundant; point mutations in any one cause constitutive SARM1 NADase activity and spontaneous NAD+/axon loss. Cryo-EM reveals a compact octamer in which TIR domains are isolated and prevented from oligomerization. Peptide mapping; cryo-EM structure of SARM1 octamer; mutagenesis of five autoinhibitory interfaces; NAD+ measurement; axon degeneration assays Proceedings of the National Academy of Sciences of the United States of America High 33468661
2019 SARM1 assembles into a homo-octameric ring structure; both SARM1 and its isolated tandem SAM1-2 domains form octamers in solution. The SAM1-2 ring is stabilized by hydrophobic 'lock-and-key' and electrostatic interactions between protomers. Mutation of SAM1-2 interface residues disrupts oligomerization and abolishes SARM1 apoptotic/degenerative activity in cells. Size-exclusion chromatography; electron microscopy; crystal structure of SAM1-2 (octameric ring in lattice); SAM interface mutagenesis; cellular death assays Journal of molecular biology High 31278906
2015 Axon degeneration induced by NMNAT2 depletion (either by injury or genetic loss) requires SARM1; SARM1 deficiency corrects axon outgrowth restriction in NMNAT2-deficient mice, preventing perinatal lethality. NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation. SARM1 acts downstream of NMNAT2 loss in a linear or convergent pathway. Genetic epistasis (SARM1 KO × NMNAT2 KO double-mutant mice); NAMPT inhibitor pharmacology; axon degeneration quantification Cell reports High 25818290
2014 Mitochondrial depolarization triggers SARM1-dependent axon degeneration and neuronal cell death in sensory neurons. SARM1 acts downstream of reactive oxygen species (ROS) generation; neurons lacking SARM1 survive despite mitochondrial depolarization, ATP depletion, calcium influx, and ROS accumulation. SARM1 also mediates neuronal death induced by prolonged ROS exposure. Pharmacological mitochondrial depolarization (CCCP) in primary mouse sensory neurons; Sarm1 KO; measurement of mitochondrial potential, ATP, Ca2+, ROS; axon degeneration and cell death quantification The Journal of neuroscience High 25009267
2020 Live imaging of single mouse sensory axons reveals that SARM1 NADase activity triggers an ordered downstream sequence: loss of cellular ATP → defects in mitochondrial movement and depolarization → calcium influx → phosphatidylserine externalization → loss of membrane permeability → catastrophic axon self-destruction. Live single-axon imaging with fluorescent reporters for ATP, mitochondria, calcium, phosphatidylserine, and membrane integrity in primary mouse neurons eLife High 34779400
2018 JNK phosphorylates SARM1 at serine 548 under oxidative stress, enhancing SARM1 NAD+ cleavage activity and inhibiting mitochondrial respiration. Non-phosphorylatable S548A mutation or JNK inhibitor decreases SARM1 activity. In vitro and cell-based phosphorylation assays; site-directed mutagenesis (S548A); JNK inhibitor treatment; NAD+ cleavage assay; mitochondrial respiration measurement The Journal of biological chemistry Medium 30333228
2020 TNF-α induces SARM1-dependent axon degeneration in a neuroinflammatory model (glaucoma) and in sensory neurons via noncanonical necroptotic signaling. MLKL (the canonical necroptosis executioner) does not directly destroy axons; instead MLKL causes loss of axon survival factors NMNAT2 and STMN2, activating SARM1 NADase, which leads to calcium influx and axon degeneration. Genetic KO of SARM1/MLKL in neuroinflammatory/necroptotic neuronal models; Western blot for NMNAT2/STMN2; SARM1 NADase activity measurement; calcium imaging The Journal of cell biology High 32609299
2013 SARM1 binds PINK1 and forms a complex with TRAF6 on depolarized mitochondria. SARM1 promotes TRAF6-mediated K63-chain ubiquitination of PINK1 at K433, stabilizing PINK1 at the outer mitochondrial membrane and enabling parkin recruitment (mitophagy). Knockdown of SARM1 or TRAF6 abrogates PINK1 accumulation and parkin recruitment. Co-immunoprecipitation of SARM1-PINK1-TRAF6 complex; ubiquitination assay; RNAi knockdown; fluorescence microscopy of parkin recruitment Molecular biology of the cell Medium 23885119
2012 Mitochondria-localized SARM promotes intrinsic apoptosis in T cells by generating ROS and depolarizing mitochondrial potential. The SAM and TIR domains mediate this proapoptotic function. SARM suppresses Bcl-xL expression and reduces ERK phosphorylation; overexpression of Bcl-xL or double KO of Bax/Bak substantially reduces SARM-induced apoptosis. SARM knockdown in T cells; SARM domain-deletion constructs; mitochondrial ROS and potential measurement; Bcl-xL overexpression; Bax/Bak double-KO rescue; caspase assays; in vivo influenza infection Cell death and differentiation Medium 23175186
2022 SARM1 regulates axon regeneration independently of its pro-degenerative NADase function. TIR-1/SARM1 cell-autonomously inhibits axon regeneration by activating the NSY-1/ASK1 MAPK cascade, while simultaneously promoting axon degeneration through the DLK-1 MAPK cascade—two distinct downstream pathways. This inhibition of regeneration is conserved in human SARM1. C. elegans tir-1 mutant analysis; genetic epistasis with ask1/dlk-1 MAPK pathway mutants; domain-specific and NADase-dead mutants; human SARM1 expression in C. elegans neurons eLife High 37083456
2021 The vacor metabolite VMN (a pyridine compound) is a potent activator of SARM1 NADase activity. Crystal structure of the Drosophila SARM1 regulatory domain complexed with VMN was determined; VMN binds the ARM allosteric pocket. Genetic deletion of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. Crystal structure of Drosophila SARM1 ARM domain-VMN complex; SARM1 NADase assay with VMN; Sarm1-KO mouse neurons in vitro and in vivo vacor treatment eLife High 34870595
2021 Nicotinic acid mononucleotide (NaMN) inhibits SARM1 activation by competing with NMN for binding to the SARM1 allosteric ARM domain site and promoting the open, autoinhibited configuration. Co-crystal structure of NaMN with the SARM1 ARM domain was determined. ARM domain co-crystal structure with NaMN; SARM1 NADase inhibition assays; axon degeneration assays Experimental neurology High 34403688
2022 Cysteine-311 (C311) in the non-catalytic ARM domain of SARM1 is an allosteric site that can be covalently targeted by tryptoline acrylamide electrophiles to inhibit SARM1 NADase activity; C311A or C311S mutants are resistant to these inhibitors. Inhibition at C311 blocks vincristine- and vacor-induced neurite degeneration. Chemical proteomics (site-specific covalent labeling); C311A/C311S mutagenesis; NADase activity assay; DRG neuron degeneration assay Proceedings of the National Academy of Sciences of the United States of America High 35994671
2020 cADPR is a direct product of SARM1 NADase activity and serves as a gene-dosage-sensitive biomarker of SARM1 enzymatic activity in neurons, sciatic nerve, and brain. SARM1 has basal activity in the absence of injury; injury triggers a dramatic SARM1-dependent cADPR increase proportional to SARM1 gene dosage. Manipulation of cADPR levels in neurons does not alter the time course of axon degeneration, indicating cADPR is not the critical effector of degeneration. cADPR measurement in DRG neurons, sciatic nerve, and brain from SARM1 WT, heterozygous, and KO mice; enzymatic cADPR manipulation; axon degeneration time course Experimental neurology High 32087251
2020 Citrate induces a phase transition (higher-order multimerization/puncta formation) of SARM1 that enhances its NADase catalytic activity ~2000-fold. A multimerization-disrupting mutation (G601P) prevents the phase transition and puncta formation in cells and ablates the activity enhancement. Citrate-induced TIR-1/SARM1 multimerization is required for axon degeneration in C. elegans. In vitro SARM1 NADase kinetic assays with citrate; G601P mutagenesis; cell puncta imaging; C. elegans tir-1 axon degeneration assay eLife High 34184985
2022 In C. elegans, a phase transition of TIR-1/SARM1 into visible puncta in intestinal epithelial cells underlies p38 PMK-1 immune pathway activation during pathogen infection or cholesterol deficiency. Oligomerization dramatically potentiates TIR-1 NAD+ glycohydrolase activity in vitro. Mutations blocking multimerization or NADase activity prevent p38 phosphorylation, immune effector expression, and increase infection susceptibility. Fluorescence imaging of TIR-1 puncta in live C. elegans; in vitro NADase kinetics; genetic mutant analysis (multimerization-null, NADase-dead); p38 phosphorylation immunoblot; infection survival assays eLife High 35098926
2014 SARM is required for CCL5 production in macrophages following TLR stimulation and cytosolic nucleic acid sensing. SARM is critical for recruitment of transcription factors and RNA polymerase II to the Ccl5 promoter, independent of effects on MAPKs, NF-κB, IRF activity, or mRNA stability. SARM-KO macrophage cytokine profiling; chromatin immunoprecipitation (ChIP) for transcription factor and Pol II recruitment at Ccl5 promoter; mRNA stability assays Journal of immunology Medium 24711619
2018 NLRX1 associates with SARM1 in the mitochondrial matrix of non-neuronal cells, and the apoptotic function of NLRX1 in these cells is fully dependent on SARM1, placing SARM1 downstream of NLRX1 in apoptosis regulation. Co-immunoprecipitation of NLRX1-SARM1; subcellular fractionation; SARM1 KO epistasis in non-neuronal apoptosis model Molecular and cellular biochemistry Medium 30191480
2022 Autophagy kinase ULK1 physically interacts with SARM1 (requiring SARM1 SAM domains) in neurons in vitro and in vivo. ULK1-SARM1 interaction increases upon neurite damage; ULK1 inhibition or knockdown attenuates SARM1 puncta accumulation in injured neurites and reduces neurite fragmentation. Co-immunoprecipitation (ULK1-SARM1); domain-deletion mutagenesis (SAM requirement); ULK1 inhibitor and Ulk1 shRNA in primary cortical neurons; in vivo SCI model with Becn1 hypomorph mice Proceedings of the National Academy of Sciences of the United States of America Medium 36375051
2021 Cryo-EM structure combined with a covalent inhibitor (NSDP, nisoldipine derivative) shows SARM1 locked in an inactive conformation with the inhibitor reacting preferentially with Cys311 in the ARM domain, blocking NMN-induced activation. Cryo-EM of SARM1-inhibitor complex; site-directed mutagenesis; SARM1 NADase activity assay; axon degeneration assay eLife High 33944777
2020 Mitochondrial impairment leads to axonal NMNAT2 depletion (via impaired synthesis and reduced axonal transport), increases the NMN/NAD+ ratio, and activates SARM1-dependent axon degeneration. This places mitochondrial dysfunction upstream of NMNAT2 loss in the Wallerian degeneration pathway. Pharmacological mitochondrial uncoupling in mouse sympathetic neurons; NMNAT2 protein measurement; WLDS expression and Sarm1 deletion as epistatic tools; Drosophila Pink1 loss-of-function genetic model Neurobiology of disease High 31740269
2013 UXT isoforms differentially regulate SARM-induced apoptosis: UXT-V1 reduces caspase-8 activity and is anti-apoptotic, while UXT-V2 strongly increases caspase-8 activity and enhances SARM-induced apoptosis via the extrinsic pathway and mitochondrial depolarization. UXT interacts with SARM by yeast two-hybrid analysis. Yeast two-hybrid (UXT-SARM interaction); caspase-8 activity assay; mitochondrial membrane potential measurement; overexpression epistasis FEBS letters Low 24021647
2023 TRPV1 binds SARM1 via its N-terminal ankyrin repeat domain interacting with the TIR-His583 domain of SARM1 to maintain hepatic stellate cell quiescence and prevent NF-κB-mediated pro-inflammatory activation. This interaction was confirmed by mass spectrometry, co-immunoprecipitation, surface plasmon resonance, BRET, and NanoBiT assays. Mass spectrometry pull-down; Co-IP; surface plasmon resonance; BRET; NanoBiT complementation; loss-of-function in HSCs; Trpv1-/- mice Journal of hepatology Medium 36669703
2024 Human SARM1 negatively regulates TLR4-dependent TNF mRNA induction in monocytes independently of its NADase activity, and inhibits IL-1β secretion through both NADase-dependent inhibition of pro-IL-1β expression and NADase-independent suppression of NLRP3 inflammasome processing of pro-IL-1β. SARM1 knockdown in human monocytes; NADase-dead SARM1 mutant; TNF and IL-1β mRNA/protein measurement; NLRP3 inflammasome activity assay iScience Medium 38832024

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron 490 28334607
2006 The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature immunology 414 16964262
2004 TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature immunology 365 15048112
2013 Sarm1-mediated axon degeneration requires both SAM and TIR interactions. The Journal of neuroscience : the official journal of the Society for Neuroscience 305 23946415
2016 Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 270 26844829
2021 SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron 233 33657413
2016 Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain : a journal of neurology 226 27797810
2015 Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell reports 164 25818290
2020 The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature 158 33053563
2017 Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy. Journal of the peripheral nervous system : JPNS 153 28485482
2014 Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 149 25009267
2021 SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. Theranostics 148 33754056
2009 The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. Journal of virology 142 19587044
2013 A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. The journal of nutrition, health & aging 131 23732550
2019 Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. JCI insight 121 31484833
2020 The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. Current opinion in neurobiology 118 32311648
2019 Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. The Journal of experimental medicine 116 30642945
2021 Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. Brain : a journal of neurology 114 33964142
2020 SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. The Journal of cell biology 113 32609299
2016 SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proceedings of the National Academy of Sciences of the United States of America 108 27671644
2010 SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. European journal of immunology 102 20306472
2019 Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration. Neurobiology of disease 98 31740269
2020 Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1. Cell reports 96 32755591
2020 Structural basis for SARM1 inhibition and activation under energetic stress. eLife 94 33185189
2003 Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biological & pharmaceutical bulletin 93 14600402
2020 cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons. Experimental neurology 86 32087251
2006 Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharmaceutical research 82 17063395
2022 Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients. Molecular neurodegeneration 80 34991663
2018 c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration. The Journal of biological chemistry 72 30333228
2012 T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell death and differentiation 71 23175186
2019 Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss. Acta neuropathologica communications 69 31661035
2007 SARM: a novel Toll-like receptor adaptor, is functionally conserved from arthropod to human. Molecular immunology 69 17980913
2019 Sarm1 deletion reduces axon damage, demyelination, and white matter atrophy after experimental traumatic brain injury. Experimental neurology 65 31445042
2020 SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration. eLife 62 33107823
2013 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Molecular biology of the cell 61 23885119
2021 Live imaging reveals the cellular events downstream of SARM1 activation. eLife 59 34779400
2019 Structural Evidence for an Octameric Ring Arrangement of SARM1. Journal of molecular biology 59 31278906
2022 Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain. Proceedings of the National Academy of Sciences of the United States of America 58 35994671
2019 Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases. Cell chemical biology 58 31761689
2021 Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate. eLife 54 33944777
2010 Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140. ACS medicinal chemistry letters 52 24900290
2022 Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition. eLife 50 35098926
2021 Multiple domain interfaces mediate SARM1 autoinhibition. Proceedings of the National Academy of Sciences of the United States of America 49 33468661
2013 Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate immunity 47 23751821
2018 GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women. The Journal of clinical endocrinology and metabolism 46 29982690
2021 Social Media, Body Image and Resistance Training: Creating the Perfect 'Me' with Dietary Supplements, Anabolic Steroids and SARM's. Sports medicine - open 45 34757466
2020 Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation. Scientific reports 44 33318563
2019 SARM: From immune regulator to cell executioner. Biochemical pharmacology 44 30633870
2020 Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies. PLoS pathogens 42 32069324
2020 Passenger Mutations Confound Phenotypes of SARM1-Deficient Mice. Cell reports 41 32268088
2021 Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1. eLife 40 34870595
2020 SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration. Life science alliance 39 32312889
2022 Multifaceted roles of SARM1 in axon degeneration and signaling. Frontiers in cellular neuroscience 38 36090788
2020 Identification of the first noncompetitive SARM1 inhibitors. Bioorganic & medicinal chemistry 38 32828421
2022 Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria. eLife 37 35285800
2021 Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed. Neuron 34 34384519
2018 The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1. Molecular and cellular biochemistry 34 30191480
2021 The forensic response after an adverse analytical finding (doping) involving a selective androgen receptor modulator (SARM) in human athlete. Journal of pharmaceutical and biomedical analysis 33 34715583
2023 Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1. Journal of hepatology 32 36669703
2021 Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures. Acta neuropathologica communications 32 34001261
2020 Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration. Communications biology 32 32001778
2024 SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease. Aging and disease 31 37307837
2021 SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration. Experimental neurology 31 33548217
2021 Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Experimental neurology 31 34403688
2018 Celastrol attenuates incision-induced inflammation and pain associated with inhibition of the NF-κB signalling pathway via SARM. Life sciences 31 29750991
2016 2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy. Journal of medicinal chemistry 31 26683992
2023 Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies. Molecular therapy. Nucleic acids 30 36950280
2021 Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice. Experimental neurology 29 33460644
2019 SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. The Journal of experimental medicine 29 30842236
2022 Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling. Cell death & disease 28 36055989
2021 A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration. eLife 28 34184985
2022 Klebsiella pneumoniae hijacks the Toll-IL-1R protein SARM1 in a type I IFN-dependent manner to antagonize host immunity. Cell reports 27 35947948
2015 Telmisartan mediates anti-inflammatory and not cognitive function through PPAR-γ agonism via SARM and MyD88 signaling. Pharmacology, biochemistry, and behavior 26 26264163
2014 SARM regulates CCL5 production in macrophages by promoting the recruitment of transcription factors and RNA polymerase II to the Ccl5 promoter. Journal of immunology (Baltimore, Md. : 1950) 26 24711619
2020 Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO molecular medicine 25 31930715
2017 Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 25 29334634
2015 MMP-12-mediated by SARM-TRIF signaling pathway contributes to IFN-γ-independent airway inflammation and AHR post RSV infection in nude mice. Respiratory research 25 25652021
2018 HPV-transformed cells exhibit altered HMGB1-TLR4/MyD88-SARM1 signaling axis. Scientific reports 24 29472602
2015 Beyond TLR Signaling—The Role of SARM in Antiviral Immune Defense, Apoptosis & Development. International reviews of immunology 24 26268046
2021 A First-in-Human Phase 1 Study of a Novel Selective Androgen Receptor Modulator (SARM), RAD140, in ER+/HER2- Metastatic Breast Cancer. Clinical breast cancer 23 34565686
2016 A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice. The Journal of steroid biochemistry and molecular biology 23 27106747
2009 Effects of selective androgen receptor modulator (SARM) treatment in osteopenic female rats. Pharmaceutical research 22 19728047
2021 CRISPR/Cas9-mediated SARM1 knockout and epitope-tagged mice reveal that SARM1 does not regulate nuclear transcription, but is expressed in macrophages. The Journal of biological chemistry 20 34793837
2022 SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration. International journal of molecular sciences 19 35163535
2022 Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury. Proceedings of the National Academy of Sciences of the United States of America 18 36375051
2015 Telmisartan attenuated LPS-induced neuroinflammation in human IMR-32 neuronal cell line via SARM in AT1R independent mechanism. Life sciences 18 25816983
2009 Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 18 18847323
2021 Functional characterization of four TIR domain-containing adaptors, MyD88, TRIF, MAL, and SARM in mandarin fish Siniperca chuatsi. Developmental and comparative immunology 17 33933533
2021 The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems. Frontiers in immunology 17 34630431
2015 In vitro metabolism studies on the selective androgen receptor modulator (SARM) LG121071 and its implementation into human doping controls using liquid chromatography-mass spectrometry. European journal of mass spectrometry (Chichester, England) 17 25906032
2024 Augustus Waller's foresight realized: SARM1 in peripheral neuropathies. Current opinion in neurobiology 16 38852438
2023 SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice. Acta physiologica (Oxford, England) 15 37186158
2018 Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls. Drug testing and analysis 15 30379415
2015 Hm-MyD88 and Hm-SARM: two key regulators of the neuroimmune system and neural repair in the medicinal leech. Scientific reports 15 25880897
2013 UXT plays dual opposing roles on SARM-induced apoptosis. FEBS letters 15 24021647
2023 TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration. eLife 14 37083456
2012 Molecular characterization of porcine SARM1 and its role in regulating TLRs signaling during highly pathogenic porcine reproductive and respiratory syndrome virus infection in vivo. Developmental and comparative immunology 14 22366489
2024 SARM1 regulates pro-inflammatory cytokine expression in human monocytes by NADase-dependent and -independent mechanisms. iScience 13 38832024
2022 SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease. Neural regeneration research 13 35259852
2017 Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f. PloS one 13 29216311