{"gene":"NMNAT2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2010,"finding":"Endogenous NMNAT2 is a labile axon survival factor that undergoes rapid proteasome-dependent turnover; its constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of NMNAT2 is sufficient to induce Wallerian-like degeneration of uninjured axons, and proteasome inhibition slows both NMNAT2 turnover and neurite degeneration.","method":"Primary neuron culture with specific Nmnat2 depletion, live neurite imaging, proteasome inhibitor treatment, half-life measurements across Nmnat isoforms","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (depletion, rescue, pharmacological inhibition), independently replicated in subsequent work","pmids":["20126265"],"is_preprint":false},{"year":2013,"finding":"NMNAT2 is bidirectionally trafficked in axons on trans-Golgi network/synaptic vesicle-associated vesicles via fast axonal transport. Palmitoylation of a double-cysteine motif (shared with GAP43) encoded by exon 6 is necessary and sufficient for stable membrane association and vesicular axonal transport. Disrupting membrane association (cytosolic mutants) increases NMNAT2 half-life and axon protective capacity, demonstrating that palmitoylation controls NMNAT2 turnover and axon protection.","method":"Dual-colour live-cell imaging of axonal transport in SCG neurons, palmitoylation mutagenesis, co-migration analysis with organelle markers, transected neurite protection assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of transport, mutagenesis of palmitoylation motif, multiple orthogonal readouts","pmids":["23610559"],"is_preprint":false},{"year":2014,"finding":"NMNAT2 palmitoylation is dynamically regulated by cytosolic thioesterases APT1 and APT2 (depalmitoylation) and by palmitoyltransferase zDHHC17 (HIP14) among several zDHHC enzymes (palmitoylation), on a time scale comparable to NMNAT2's short half-life. Palmitoylation-independent membrane attachment is mediated by the same minimal domain required for palmitoylation.","method":"Biochemical identification of palmitoyltransferases and thioesterases acting on NMNAT2, palmitoylation assays, subcellular localization studies, half-life measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic identification with multiple zDHHC candidates tested, single lab with multiple orthogonal methods","pmids":["25271157"],"is_preprint":false},{"year":2015,"finding":"Axon degeneration induced by NMNAT2 depletion requires SARM1 and is therefore downstream of NMNAT2 loss. Genetic SARM1 deficiency also corrects restricted axon outgrowth in NMNAT2-deficient mice independently of NMNAT metabolites. NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation as the pro-degenerative signal downstream of NMNAT2 loss.","method":"Genetic epistasis in NMNAT2/SARM1 double-knockout mice, metabolite measurements in injured axons, NAMPT inhibitor treatment, axon outgrowth assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO mice, metabolite profiling, pharmacological rescue, replicated across multiple contexts","pmids":["25818290"],"is_preprint":false},{"year":2013,"finding":"NMNAT2 is required in vivo for axon extension during embryonic development; Nmnat2 gene-trap mice die perinatally with severe peripheral and CNS axon truncation due to limited axon extension (not dying-back degeneration). WldS protein can substitute for NMNAT2 loss and rescue developmental defects in a dose-dependent manner.","method":"Nmnat2 gene-trap mouse generation, embryonic histology, PNS/CNS neuronal cultures, WldS genetic rescue","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with histological and behavioral phenotyping, genetic rescue with WldS, replicated by independent Blad mouse study","pmids":["23946398"],"is_preprint":false},{"year":2016,"finding":"NMNAT2 forms a complex with HSP90 to perform a chaperone (refoldase) function, independent of its NAD-synthesizing enzymatic activity. This chaperone function requires a unique C-terminal ATP site activated in the presence of HSP90. NMNAT2 acts as a chaperone to reduce proteotoxic stress while its enzymatic activity protects against excitotoxicity, demonstrating context-dependent dual functions.","method":"Co-immunoprecipitation of NMNAT2-HSP90 complex, in vitro refoldase assay, C-terminal ATP site mutagenesis, cortical neuron deletion/stress assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical complex identification with Co-IP, in vitro enzymatic assay, active-site mutagenesis, single lab with multiple orthogonal methods","pmids":["27254664"],"is_preprint":false},{"year":2017,"finding":"MAPK signaling promotes axon degeneration by accelerating NMNAT2 turnover. MAPK signaling functions upstream of SARM1 (not downstream) by limiting NMNAT2 levels, thereby promoting SARM1 activation after injury. Loss of MAPK signaling increases NMNAT2 levels and is required for the axon protection conferred by MAPK inhibition.","method":"Cultured mammalian neurons and Drosophila motor neurons, MAPK pathway inhibition/activation, NMNAT2 protein half-life measurements, SARM1 epistasis experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis experiments placing MAPK upstream of SARM1 via NMNAT2, validated in two organisms with multiple methods","pmids":["28095293"],"is_preprint":false},{"year":2018,"finding":"The human PHR E3 ubiquitin ligase PAM (MYCBP2) forms an atypical SCF-like complex with FBXO45 and SKP1 (but lacking CUL1) that polyubiquitinates NMNAT2, promoting its proteasomal degradation. FBXO45 is important for complex assembly, and SKP1 acts as an auxiliary component enhancing FBXO45 binding to NMNAT2.","method":"Biochemical complex characterization, Co-IP, in vitro ubiquitination assay, proteasome degradation assay, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution, Co-IP for complex assembly, single lab with multiple orthogonal methods","pmids":["29997255"],"is_preprint":false},{"year":2016,"finding":"SKP1 (Skp1a), a core component of an atypical SCF-type E3 ubiquitin ligase complex, regulates NMNAT2 protein levels in axons. Skp1a depletion elevates axonal NMNAT2, prolonging axonal ATP maintenance and delaying axon degeneration after injury in vitro and in the optic nerve in vivo. Skp1a knockdown fails to protect axons from Nmnat2 knockdown, placing Skp1a function upstream of NMNAT2.","method":"Skp1a knockdown in mammalian neurons, axon degeneration assays in vitro and in vivo (optic nerve), NMNAT2 protein level measurement, epistasis with NMNAT2 knockdown, ATP measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis experiment, in vivo optic nerve model, ATP measurement linking mechanism to degeneration, consistent with independent PAM/FBXO45 work","pmids":["27732853"],"is_preprint":false},{"year":2025,"finding":"FBXO21 forms an SCFFBXO21 complex (with SKP1, CUL1, and RBX1) that ubiquitinates NMNAT2 at lysine K155 within its isoform-specific targeting and interaction domain (ISTID), promoting proteasomal degradation. Ubiquitination-deficient NMNAT2-K155R exhibits markedly reduced turnover and enhanced axon protection. FBXO21 knockout mice show elevated NMNAT2 levels and prolonged survival of injured sciatic nerves.","method":"Co-IP for complex identification, in vitro and in vivo ubiquitination assay, site-directed mutagenesis (K155R), FBXO21 knockout mouse sciatic nerve injury model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of ubiquitination, site-specific mutagenesis, in vivo KO with nerve injury readout, multiple orthogonal methods","pmids":["41026098"],"is_preprint":false},{"year":2009,"finding":"NMNAT2 delays Wallerian degeneration in SCG neurons, and this axon-protective function depends on its NAD synthesis enzymatic activity; mutation of the conserved enzymatic active site disrupts both enzyme activity and axon protection.","method":"SCG primary culture axon degeneration assay, active-site mutagenesis, NAD synthesis activity measurement","journal":"Neurochemistry international","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic active-site mutagenesis with functional axon protection readout, single lab","pmids":["19778564"],"is_preprint":false},{"year":2017,"finding":"NMN deamidase, a bacterial enzyme that consumes NMN without synthesizing NAD, delays axon degeneration in mice and zebrafish and rescues axon outgrowth defects and perinatal lethality in NMNAT2-deficient mice, supporting that NMN accumulation (rather than NAD deficit alone) is pro-degenerative downstream of NMNAT2 loss.","method":"Transgenic NMN deamidase expression in zebrafish and mice, NMNAT2 KO rescue experiment, NMN measurement in sciatic nerve","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic rescue in two species with quantitative metabolite measurement, orthogonal to NAMPT inhibition data","pmids":["28262487"],"is_preprint":false},{"year":2019,"finding":"Mitochondrial membrane potential disruption leads to axonal NMNAT2 depletion in mouse sympathetic neurons via impaired NMNAT2 synthesis and reduced axonal transport, increasing NMN/NAD ratio. WldS expression and Sarm1 deletion both protect axons after mitochondrial uncoupling, placing NMNAT2 loss upstream of SARM1 activation in mitochondrial-stress-induced Wallerian degeneration.","method":"Mitochondrial uncoupler treatment of mouse SCG neurons, NMNAT2 protein/transport measurement, NMN/NAD ratio assay, WldS expression and Sarm1-KO rescue, Pink1 fly model lifespan assay","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — metabolite profiling, transport assay, genetic rescue with WldS and Sarm1 deletion, cross-species validation in Drosophila","pmids":["31740269"],"is_preprint":false},{"year":2024,"finding":"NMNAT2 maintains NAD redox potential in distal axons to support vesicular glycolysis providing on-board ATP for fast axonal transport. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. SARM1 reduction (not NAD+ supplementation) rescues mitochondrial function in NMNAT2 KO neurons, indicating SARM1 mediates the mitochondrial dysfunction downstream of NMNAT2 loss.","method":"NMNAT2 conditional KO mouse model, live axonal transport imaging, glycolysis/OXPHOS metabolic assays, NAD+ sensor imaging, antisense oligonucleotides for SARM1 knockdown, Seahorse metabolic flux","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, metabolic flux, genetic and pharmacological rescue), in vivo and in vitro consistency","pmids":["38282024"],"is_preprint":false},{"year":2013,"finding":"Deletion of central ISTID sequences (including the palmitoylation domain) abolishes vesicle association, increases NMNAT2 protein stability in peripheral axons in vivo, and enhances axon protective capacity both in mouse and Drosophila, establishing that ISTID-mediated membrane tethering controls NMNAT2 turnover in vivo.","method":"Transgenic fluorescently tagged NMNAT2 with ISTID deletions in mouse sciatic nerve, Drosophila ORN axon protection assay in vivo, protein stability measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse and Drosophila models with domain deletion, single lab, consistent with in vitro palmitoylation data","pmids":["23995269"],"is_preprint":false},{"year":2011,"finding":"NMNAT2 transcription is directly regulated by CREB via two functional CRE sites in the nmnat2 promoter. In tauopathy (rTg4510) mice, reduced pCREB binding to these CRE sites precedes neurodegeneration and correlates with decreased NMNAT2 mRNA and protein. AAV-mediated NMNAT2 overexpression reduces neurodegeneration in rTg4510 hippocampi.","method":"CRE site identification, EMSA/ChIP for pCREB binding, rTg4510 mouse model, AAV-mediated NMNAT2 overexpression, histological neurodegeneration quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP for direct CRE binding, in vivo AAV rescue, single lab","pmids":["22027994"],"is_preprint":false},{"year":2013,"finding":"NMNAT2 activates protein phosphatase 2A (PP2A), reducing tau phosphorylation at multiple AD-associated sites. Overexpression of NMNAT2 activates PP2A with attenuation of tau phosphorylation; NMNAT2 shRNA knockdown inhibits PP2A and causes tau hyperphosphorylation. PP2A inhibition abolishes NMNAT2-induced tau dephosphorylation.","method":"HEK293/tau cell overexpression and shRNA knockdown, PP2A activity assay, okadaic acid (PP2A inhibitor) epistasis, tau phosphorylation western blot at multiple sites","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based gain/loss-of-function with PP2A inhibitor epistasis, single lab, no direct physical interaction demonstrated","pmids":["23579329"],"is_preprint":false},{"year":2012,"finding":"NMNAT2 overexpression blocks angiotensin II-induced cardiac hypertrophy in neonatal rat cardiomyocytes through activation of SIRT6 by maintaining intracellular NAD levels. A catalytically inactive NMNAT2 mutant does not block hypertrophy, demonstrating dependence on enzymatic NAD synthesis activity.","method":"Neonatal rat cardiomyocyte overexpression with catalytically inactive mutant, Ang II hypertrophy model, SIRT6 activity measurement, NAD level assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant used to establish enzymatic dependence, SIRT6 activity measured, single lab","pmids":["22449973"],"is_preprint":false},{"year":2013,"finding":"SIRT3 interacts with and deacetylates NMNAT2, and this interaction regulates NMNAT2 NAD+ synthesis activity. Downregulation of SIRT3 inhibits NMNAT2 deacetylation and reduces NAD+ synthesis activity in NSCLC cells.","method":"Yeast two-hybrid screen, Co-IP in vitro and in vivo, deacetylation assay, NAD+ synthesis activity measurement — NOTE: This paper (PMID:24042441) was subsequently retracted (PMID:37026521) due to data integrity concerns","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — paper retracted; data integrity compromised; findings cannot be relied upon","pmids":["24042441","37026521"],"is_preprint":false},{"year":2014,"finding":"NMNAT2 expression is induced upon DNA damage in a p53-dependent manner. Two functional p53 binding sites within the human NMNAT2 gene were identified and validated. NMNAT2 knockdown reduces cellular NAD+ levels and protects cells from p53-dependent cell death upon DNA damage, indicating NMNAT2 mediates p53-dependent metabolic and cell-death signaling.","method":"p53 binding site identification and reporter assay, DNA damage treatment with p53-dependent induction, NMNAT2 knockdown with NAD+ measurement, cell death assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional p53 binding sites validated in reporter assay, knockdown with NAD+ and cell viability readouts, single lab","pmids":["24552824"],"is_preprint":false},{"year":2019,"finding":"NMNAT2-deficient oocytes have disturbed meiotic apparatus assembly and elevated ROS. SIRT1 activation or overexpression partially prevents meiotic defects caused by NMNAT2 depletion, establishing a NMNAT2-NAD+-SIRT1 pathway controlling redox homeostasis during oocyte meiotic maturation.","method":"NMNAT2-specific depletion in mouse oocytes, spindle/chromosome assembly assay, ROS measurement, SIRT1 genetic and pharmacological rescue","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific depletion with defined cellular phenotype, genetic epistasis via SIRT1 rescue, single lab","pmids":["30909324"],"is_preprint":false},{"year":2024,"finding":"Chronically low NMNAT2 levels lead to sub-lethal SARM1 activation in morphologically intact axons, characterized by NAD(P) depletion and compromised neurite outgrowth, without overt axon degeneration. Low NMNAT2 reverses the NAD-enhancing effect of nicotinamide riboside in axons in a SARM1-dependent manner.","method":"Compound heterozygote NMNAT2 mice, SCG primary cultures, NAD(P) measurement, neurite outgrowth assay, SARM1 genetic deletion epistasis, nicotinamide riboside treatment","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with SARM1 deletion, multiple metabolite and morphological readouts, single lab","pmids":["39352636"],"is_preprint":false},{"year":2021,"finding":"NMNAT2 suppresses amyloid-beta production and upregulates alpha-secretase ADAM10 via an AMPK-dependent mechanism. Overexpression of NMNAT2 increases the NAD+/NADH ratio, activates AMPK, and increases ADAM10 mRNA and activity; this effect is abolished by the AMPK antagonist Compound C.","method":"N2a/APPswe cell overexpression, AMPK inhibitor (Compound C) epistasis, ADAM10 activity assay, Abeta measurement, NAD+/NADH ratio","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-based overexpression with pharmacological epistasis, single lab, no direct NMNAT2-AMPK interaction demonstrated","pmids":["34644262"],"is_preprint":false},{"year":2026,"finding":"In DRG neurons, the Raf-MEK-ERK cascade upregulates Nmnat2 via ERK phosphorylation-dependent transcription, maintaining axon survival. MEK inhibition decreases Nmnat2 expression and induces axon degeneration in DRG neurons, rescued by Nmnat2 overexpression. Cortical and spinal neurons maintain Nmnat2 via CREB (independent of MEK-ERK), demonstrating neuron subtype-specific transcriptional regulation of Nmnat2.","method":"MEK inhibitor treatment of DRG/cortical/spinal neurons, Nmnat2 mRNA/protein quantification, ERK phosphorylation assays, Nmnat2 overexpression rescue, axon degeneration assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ERK-dependent transcription with rescue by Nmnat2 overexpression, neuron-type comparison, single lab","pmids":["41619208"],"is_preprint":false},{"year":2025,"finding":"ATF4, ATF6, SOX11, and HSF1 are required for NMNAT2 transcription in SH-SY5Y cells; specific genomic regulatory regions identified by 4C-seq (chromosome conformation capture) interact with the NMNAT2 promoter in undifferentiated versus neuron-like states. CRISPR-Cas9 deletion of two regulatory regions confirmed their requirement for NMNAT2 transcription.","method":"4C-seq, CRISPR-Cas9 deletion of regulatory regions, luciferase reporter assays, transcription factor knockdown/overexpression in SH-SY5Y cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR validation of regulatory regions, TF requirement confirmed functionally, single lab with multiple orthogonal methods","pmids":["41241829"],"is_preprint":false},{"year":2019,"finding":"Human NMNAT2 missense mutations (compound heterozygous in FADS patients; homozygous T94M in polyneuropathy/erythromelalgia patients) cause partial or complete loss of function in both NAD+ synthesis and chaperone functions. The T94M substitution confers reduced ability to support axon survival in mouse primary neuron cultures and has altered enzymatic properties, establishing NMNAT2 as the causative gene in these human axonal disorders.","method":"Patient exome sequencing, mouse primary neuron axon survival assay with mutant overexpression, in vitro NAD+ synthesis assay, protein stability assay, chaperone function assay","journal":"Experimental neurology / Experimental neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple functional assays (enzymatic, chaperone, axon survival) on patient-derived variants, two independent patient studies with consistent findings","pmids":["31136762","31132363"],"is_preprint":false}],"current_model":"NMNAT2 is a labile, palmitoylated NAD+-synthesizing enzyme that is constitutively transported anterogradely on trans-Golgi-derived vesicles into axons; its rapid turnover (controlled by an atypical SCF ubiquitin ligase complex containing PAM/MYCBP2–FBXO45–SKP1 and a separate SCFFBXO21 complex that ubiquitinates K155) means that axon survival depends on continuous resupply, and when NMNAT2 falls below a threshold—due to injury, MAPK-accelerated degradation, or reduced transcription (regulated by CREB, ERK-dependent pathways, ATF4/ATF6/SOX11/HSF1)—NMN accumulates and allosterically activates the NAD+ hydrolase SARM1, triggering axon degeneration; additionally, NMNAT2 functions as an HSP90-dependent molecular chaperone (via a C-terminal ATP site) to refold misfolded proteins, and regulates downstream effectors including SIRT6, PP2A, and AMPK to protect neurons from hypertrophy, tau phosphorylation, and amyloidogenesis."},"narrative":{"mechanistic_narrative":"NMNAT2 is a labile NAD+-synthesizing enzyme that functions as an essential axon survival and maintenance factor, constitutively replenished by fast anterograde axonal transport such that its continuous resupply is rate-limiting for axon integrity [PMID:20126265, PMID:19778564]. It is trafficked bidirectionally on trans-Golgi network/vesicle-associated carriers, and palmitoylation of a double-cysteine motif within its isoform-specific targeting and interaction domain (ISTID) drives stable membrane association and vesicular transport while simultaneously controlling its rapid turnover; disrupting membrane tethering stabilizes the protein and enhances its axon-protective capacity [PMID:23610559, PMID:23995269]. Palmitoylation is dynamically set by zDHHC17/HIP14 and the thioesterases APT1/APT2 on a timescale matched to NMNAT2's short half-life [PMID:25271157]. Its instability is enforced by proteasomal degradation through an atypical PHR/SCF-type ubiquitin ligase comprising MYCBP2(PAM)–FBXO45–SKP1 and a distinct SCF^FBXO21 (SKP1–CUL1–RBX1) complex that ubiquitinates lysine K155 within the ISTID; loss of either degradation route elevates NMNAT2 and protects injured axons [PMID:29997255, PMID:27732853, PMID:41026098]. When NMNAT2 falls below threshold—via injury, MAPK-accelerated turnover, mitochondrial stress, or reduced transcription—accumulating NMN drives activation of the pro-degenerative NAD+ hydrolase SARM1, and axon degeneration downstream of NMNAT2 loss genetically requires SARM1 [PMID:25818290, PMID:28095293, PMID:28262487, PMID:31740269]. Mechanistically, NMNAT2-maintained NAD redox potential supports vesicular glycolysis that powers fast axonal transport in distal axons [PMID:38282024]. NMNAT2 is required in vivo for developmental axon extension, and its transcription is governed in a neuron-subtype-specific manner by CREB, Raf-MEK-ERK signaling, and the factors ATF4/ATF6/SOX11/HSF1 [PMID:23946398, PMID:22027994, PMID:41619208, PMID:41241829]. Beyond its enzymatic role, NMNAT2 acts as an HSP90-dependent refoldase via a unique C-terminal ATP site, providing an enzyme-independent chaperone activity against proteotoxic stress [PMID:27254664]. Loss-of-function NMNAT2 mutations cause human axonal disorders including fetal akinesia deformation sequence and a polyneuropathy/erythromelalgia syndrome [PMID:31136762, PMID:31132363].","teleology":[{"year":2009,"claim":"Established that NMNAT2's axon-protective capacity depends on its NAD-synthesizing catalytic activity, framing the protein as an enzyme acting within neurons rather than merely a structural factor.","evidence":"Active-site mutagenesis with NAD synthesis and axon degeneration readouts in SCG primary cultures","pmids":["19778564"],"confidence":"High","gaps":["Did not address endogenous turnover or transport","Mechanism linking NAD synthesis to protection not yet defined"]},{"year":2010,"claim":"Identified endogenous NMNAT2 as an intrinsically labile axon survival factor whose continuous transport-dependent resupply is rate-limiting, explaining why axons degenerate when supply is interrupted.","evidence":"Specific Nmnat2 depletion, live neurite imaging, proteasome inhibition and half-life measurements in primary neurons","pmids":["20126265"],"confidence":"High","gaps":["Degradation machinery not identified","Downstream degeneration effector unknown"]},{"year":2013,"claim":"Defined how NMNAT2 is delivered to and turned over in axons, showing palmitoylation of an ISTID double-cysteine motif controls vesicular transport and instability.","evidence":"Dual-colour axonal transport imaging, palmitoylation mutagenesis, and transected neurite protection assays in SCG neurons; in vivo ISTID-deletion transgenics in mouse and Drosophila","pmids":["23610559","23995269"],"confidence":"High","gaps":["Enzymes setting palmitoylation not yet identified","Link between membrane tethering and degradation machinery undefined"]},{"year":2013,"claim":"Demonstrated an in vivo requirement for NMNAT2 in developmental axon extension, distinguishing this from dying-back degeneration and showing WldS can substitute.","evidence":"Nmnat2 gene-trap mice, embryonic histology, PNS/CNS cultures, WldS genetic rescue","pmids":["23946398"],"confidence":"High","gaps":["Did not resolve degenerative effector downstream of NMNAT2 loss","Metabolite basis of rescue not established"]},{"year":2014,"claim":"Identified the palmitoylation/depalmitoylation cycle (zDHHC17 vs APT1/APT2) that dynamically regulates NMNAT2 membrane association on a timescale matching its half-life.","evidence":"Enzymatic identification of palmitoyltransferases and thioesterases, palmitoylation and half-life assays","pmids":["25271157"],"confidence":"High","gaps":["In vivo relevance of specific zDHHC/APT enzymes not tested","Coupling to ubiquitin-proteasome pathway unresolved"]},{"year":2015,"claim":"Placed SARM1 genetically downstream of NMNAT2 loss and implicated NMN accumulation as the pro-degenerative signal, defining the core axon-destruction axis.","evidence":"NMNAT2/SARM1 double-knockout epistasis, metabolite profiling, NAMPT inhibition rescue, axon outgrowth assays","pmids":["25818290"],"confidence":"High","gaps":["Direct biochemical link between NMN and SARM1 not shown here","Threshold dynamics not quantified"]},{"year":2016,"claim":"Revealed an enzyme-independent chaperone (refoldase) function of NMNAT2 via a C-terminal ATP site and HSP90 partnership, establishing dual context-dependent functions.","evidence":"NMNAT2-HSP90 Co-IP, in vitro refoldase assay, C-terminal ATP-site mutagenesis, cortical neuron stress assays","pmids":["27254664"],"confidence":"High","gaps":["Physiological substrates of the chaperone activity not identified","Relative contribution in vivo unquantified"]},{"year":2016,"claim":"Identified SKP1 as a core component of an atypical SCF-type ligase controlling axonal NMNAT2 levels, with depletion protecting axons upstream of NMNAT2.","evidence":"Skp1a knockdown, in vitro and in vivo (optic nerve) degeneration assays, epistasis with Nmnat2 knockdown, ATP measurement","pmids":["27732853"],"confidence":"High","gaps":["Full ligase composition not resolved in this study","Ubiquitination site not mapped"]},{"year":2017,"claim":"Characterized the atypical PHR (MYCBP2/PAM)–FBXO45–SKP1 SCF-like ligase that polyubiquitinates NMNAT2 for degradation, identifying a specific degradation machinery.","evidence":"Complex Co-IP, in vitro ubiquitination and proteasome degradation assays, domain mapping","pmids":["29997255"],"confidence":"High","gaps":["In vivo neuronal requirement not established here","Target lysine residues not mapped"]},{"year":2017,"claim":"Positioned MAPK signaling upstream of SARM1 by showing it accelerates NMNAT2 turnover, integrating injury signaling into the NMNAT2-SARM1 axis.","evidence":"MAPK inhibition/activation, NMNAT2 half-life measurement, SARM1 epistasis in mammalian and Drosophila neurons","pmids":["28095293"],"confidence":"High","gaps":["Direct MAPK substrate in the turnover pathway not identified","Connection to specific E3 ligase undefined"]},{"year":2017,"claim":"Confirmed NMN accumulation, not NAD deficit alone, as the pro-degenerative trigger by rescuing NMNAT2-deficient phenotypes with NMN-consuming deamidase.","evidence":"Transgenic NMN deamidase in zebrafish and mice, NMNAT2 KO rescue, NMN measurement","pmids":["28262487"],"confidence":"High","gaps":["Does not address contributions of NAD in other contexts","SARM1 activation mechanism by NMN not biochemically shown here"]},{"year":2019,"claim":"Linked mitochondrial stress to Wallerian-type degeneration through NMNAT2 depletion upstream of SARM1, broadening the upstream triggers of the axis.","evidence":"Mitochondrial uncoupler treatment of SCG neurons, NMNAT2/transport and NMN/NAD measurement, WldS and Sarm1-KO rescue, Pink1 fly model","pmids":["31740269"],"confidence":"High","gaps":["Mechanism reducing NMNAT2 synthesis/transport not fully defined","Crosstalk with proteostatic degradation unexplored"]},{"year":2024,"claim":"Explained how NMNAT2-maintained NAD redox supports vesicular glycolysis to power fast axonal transport, providing a metabolic mechanism for its maintenance role.","evidence":"NMNAT2 conditional KO, live transport imaging, NAD+ sensor, Seahorse flux, SARM1 ASO knockdown","pmids":["38282024"],"confidence":"High","gaps":["Glycolytic machinery on vesicles not fully defined","Quantitative link between NAD level and transport speed incomplete"]},{"year":2024,"claim":"Showed chronically low NMNAT2 causes sub-lethal SARM1 activation in intact axons, defining a threshold-dependent pre-degenerative state relevant to disease.","evidence":"Compound heterozygote NMNAT2 mice, NAD(P) and neurite outgrowth assays, SARM1 deletion epistasis, nicotinamide riboside treatment","pmids":["39352636"],"confidence":"Medium","gaps":["Long-term consequences of sub-lethal activation not established","Single lab"]},{"year":2025,"claim":"Identified SCF^FBXO21 as a second ubiquitin ligase targeting NMNAT2 at K155 within the ISTID, mapping a defined degron and confirming in vivo relevance.","evidence":"Co-IP, in vitro/in vivo ubiquitination, K155R mutagenesis, FBXO21 KO mouse sciatic nerve injury","pmids":["41026098"],"confidence":"High","gaps":["Relative contribution versus PHR/FBXO45 ligase unresolved","Regulation of FBXO21 activity unknown"]},{"year":2025,"claim":"Defined a multi-factor transcriptional control of NMNAT2 (ATF4/ATF6/SOX11/HSF1) acting through specific chromatin-looping regulatory regions, refining how NMNAT2 levels are set.","evidence":"4C-seq, CRISPR deletion of regulatory regions, luciferase reporters, TF perturbation in SH-SY5Y cells","pmids":["41241829"],"confidence":"Medium","gaps":["In vivo neuronal relevance not tested","Integration with CREB/ERK inputs unresolved"]},{"year":2026,"claim":"Demonstrated neuron-subtype-specific transcriptional regulation, with Raf-MEK-ERK driving Nmnat2 in DRG neurons while CREB operates in cortical/spinal neurons.","evidence":"MEK inhibition, ERK phosphorylation and Nmnat2 mRNA/protein assays, Nmnat2 overexpression rescue across neuron types","pmids":["41619208"],"confidence":"Medium","gaps":["Direct transcription factor mediating ERK input not pinned","Cross-talk with degradation control unexplored"]},{"year":null,"claim":"How the multiple degradation, palmitoylation, and transcriptional inputs are integrated to set the NMNAT2 threshold that gates SARM1 activation in different neuron types and disease states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of NMNAT2 supply-versus-degradation balance","Relative weighting of PHR/FBXO45 vs SCF^FBXO21 ligases in vivo unknown","Physiological chaperone substrates and their disease relevance undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10,0,17]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[5]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,14]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,13,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,9,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":["MYCBP2(PAM)–FBXO45–SKP1 SCF-like ligase","SCF^FBXO21 (SKP1–CUL1–RBX1)","NMNAT2–HSP90 chaperone complex"],"partners":["SARM1","HSP90","MYCBP2","FBXO45","SKP1","FBXO21","ZDHHC17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZQ4","full_name":"Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2","aliases":["Nicotinamide mononucleotide adenylyltransferase 2","NMN adenylyltransferase 2","Nicotinate-nucleotide adenylyltransferase 2","NaMN adenylyltransferase 2"],"length_aa":307,"mass_kda":34.4,"function":"Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor (By similarity). 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Also acts as an activator of ADP-ribosylation by supporting the catalytic activity of PARP16 and promoting mono-ADP-ribosylation of ribosomes by PARP16 (PubMed:34314702). May be involved in the maintenance of axonal integrity (By similarity)","subcellular_location":"Golgi apparatus membrane; Cytoplasmic vesicle membrane; Cytoplasm; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q9BZQ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NMNAT2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NMNAT2","total_profiled":1310},"omim":[{"mim_id":"616143","title":"LYSOPHOSPHOLIPASE II; LYPLA2","url":"https://www.omim.org/entry/616143"},{"mim_id":"608702","title":"NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 3; NMNAT3","url":"https://www.omim.org/entry/608702"},{"mim_id":"608701","title":"NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 2; 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Specific depletion of NMNAT2 is sufficient to induce Wallerian-like degeneration of uninjured axons, and proteasome inhibition slows both NMNAT2 turnover and neurite degeneration.\",\n      \"method\": \"Primary neuron culture with specific Nmnat2 depletion, live neurite imaging, proteasome inhibitor treatment, half-life measurements across Nmnat isoforms\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (depletion, rescue, pharmacological inhibition), independently replicated in subsequent work\",\n      \"pmids\": [\"20126265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMNAT2 is bidirectionally trafficked in axons on trans-Golgi network/synaptic vesicle-associated vesicles via fast axonal transport. Palmitoylation of a double-cysteine motif (shared with GAP43) encoded by exon 6 is necessary and sufficient for stable membrane association and vesicular axonal transport. Disrupting membrane association (cytosolic mutants) increases NMNAT2 half-life and axon protective capacity, demonstrating that palmitoylation controls NMNAT2 turnover and axon protection.\",\n      \"method\": \"Dual-colour live-cell imaging of axonal transport in SCG neurons, palmitoylation mutagenesis, co-migration analysis with organelle markers, transected neurite protection assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of transport, mutagenesis of palmitoylation motif, multiple orthogonal readouts\",\n      \"pmids\": [\"23610559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMNAT2 palmitoylation is dynamically regulated by cytosolic thioesterases APT1 and APT2 (depalmitoylation) and by palmitoyltransferase zDHHC17 (HIP14) among several zDHHC enzymes (palmitoylation), on a time scale comparable to NMNAT2's short half-life. Palmitoylation-independent membrane attachment is mediated by the same minimal domain required for palmitoylation.\",\n      \"method\": \"Biochemical identification of palmitoyltransferases and thioesterases acting on NMNAT2, palmitoylation assays, subcellular localization studies, half-life measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic identification with multiple zDHHC candidates tested, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25271157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Axon degeneration induced by NMNAT2 depletion requires SARM1 and is therefore downstream of NMNAT2 loss. Genetic SARM1 deficiency also corrects restricted axon outgrowth in NMNAT2-deficient mice independently of NMNAT metabolites. NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation as the pro-degenerative signal downstream of NMNAT2 loss.\",\n      \"method\": \"Genetic epistasis in NMNAT2/SARM1 double-knockout mice, metabolite measurements in injured axons, NAMPT inhibitor treatment, axon outgrowth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO mice, metabolite profiling, pharmacological rescue, replicated across multiple contexts\",\n      \"pmids\": [\"25818290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMNAT2 is required in vivo for axon extension during embryonic development; Nmnat2 gene-trap mice die perinatally with severe peripheral and CNS axon truncation due to limited axon extension (not dying-back degeneration). WldS protein can substitute for NMNAT2 loss and rescue developmental defects in a dose-dependent manner.\",\n      \"method\": \"Nmnat2 gene-trap mouse generation, embryonic histology, PNS/CNS neuronal cultures, WldS genetic rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with histological and behavioral phenotyping, genetic rescue with WldS, replicated by independent Blad mouse study\",\n      \"pmids\": [\"23946398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NMNAT2 forms a complex with HSP90 to perform a chaperone (refoldase) function, independent of its NAD-synthesizing enzymatic activity. This chaperone function requires a unique C-terminal ATP site activated in the presence of HSP90. NMNAT2 acts as a chaperone to reduce proteotoxic stress while its enzymatic activity protects against excitotoxicity, demonstrating context-dependent dual functions.\",\n      \"method\": \"Co-immunoprecipitation of NMNAT2-HSP90 complex, in vitro refoldase assay, C-terminal ATP site mutagenesis, cortical neuron deletion/stress assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical complex identification with Co-IP, in vitro enzymatic assay, active-site mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27254664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAPK signaling promotes axon degeneration by accelerating NMNAT2 turnover. MAPK signaling functions upstream of SARM1 (not downstream) by limiting NMNAT2 levels, thereby promoting SARM1 activation after injury. Loss of MAPK signaling increases NMNAT2 levels and is required for the axon protection conferred by MAPK inhibition.\",\n      \"method\": \"Cultured mammalian neurons and Drosophila motor neurons, MAPK pathway inhibition/activation, NMNAT2 protein half-life measurements, SARM1 epistasis experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis experiments placing MAPK upstream of SARM1 via NMNAT2, validated in two organisms with multiple methods\",\n      \"pmids\": [\"28095293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The human PHR E3 ubiquitin ligase PAM (MYCBP2) forms an atypical SCF-like complex with FBXO45 and SKP1 (but lacking CUL1) that polyubiquitinates NMNAT2, promoting its proteasomal degradation. FBXO45 is important for complex assembly, and SKP1 acts as an auxiliary component enhancing FBXO45 binding to NMNAT2.\",\n      \"method\": \"Biochemical complex characterization, Co-IP, in vitro ubiquitination assay, proteasome degradation assay, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution, Co-IP for complex assembly, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29997255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SKP1 (Skp1a), a core component of an atypical SCF-type E3 ubiquitin ligase complex, regulates NMNAT2 protein levels in axons. Skp1a depletion elevates axonal NMNAT2, prolonging axonal ATP maintenance and delaying axon degeneration after injury in vitro and in the optic nerve in vivo. Skp1a knockdown fails to protect axons from Nmnat2 knockdown, placing Skp1a function upstream of NMNAT2.\",\n      \"method\": \"Skp1a knockdown in mammalian neurons, axon degeneration assays in vitro and in vivo (optic nerve), NMNAT2 protein level measurement, epistasis with NMNAT2 knockdown, ATP measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis experiment, in vivo optic nerve model, ATP measurement linking mechanism to degeneration, consistent with independent PAM/FBXO45 work\",\n      \"pmids\": [\"27732853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO21 forms an SCFFBXO21 complex (with SKP1, CUL1, and RBX1) that ubiquitinates NMNAT2 at lysine K155 within its isoform-specific targeting and interaction domain (ISTID), promoting proteasomal degradation. Ubiquitination-deficient NMNAT2-K155R exhibits markedly reduced turnover and enhanced axon protection. FBXO21 knockout mice show elevated NMNAT2 levels and prolonged survival of injured sciatic nerves.\",\n      \"method\": \"Co-IP for complex identification, in vitro and in vivo ubiquitination assay, site-directed mutagenesis (K155R), FBXO21 knockout mouse sciatic nerve injury model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of ubiquitination, site-specific mutagenesis, in vivo KO with nerve injury readout, multiple orthogonal methods\",\n      \"pmids\": [\"41026098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NMNAT2 delays Wallerian degeneration in SCG neurons, and this axon-protective function depends on its NAD synthesis enzymatic activity; mutation of the conserved enzymatic active site disrupts both enzyme activity and axon protection.\",\n      \"method\": \"SCG primary culture axon degeneration assay, active-site mutagenesis, NAD synthesis activity measurement\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic active-site mutagenesis with functional axon protection readout, single lab\",\n      \"pmids\": [\"19778564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMN deamidase, a bacterial enzyme that consumes NMN without synthesizing NAD, delays axon degeneration in mice and zebrafish and rescues axon outgrowth defects and perinatal lethality in NMNAT2-deficient mice, supporting that NMN accumulation (rather than NAD deficit alone) is pro-degenerative downstream of NMNAT2 loss.\",\n      \"method\": \"Transgenic NMN deamidase expression in zebrafish and mice, NMNAT2 KO rescue experiment, NMN measurement in sciatic nerve\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic rescue in two species with quantitative metabolite measurement, orthogonal to NAMPT inhibition data\",\n      \"pmids\": [\"28262487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mitochondrial membrane potential disruption leads to axonal NMNAT2 depletion in mouse sympathetic neurons via impaired NMNAT2 synthesis and reduced axonal transport, increasing NMN/NAD ratio. WldS expression and Sarm1 deletion both protect axons after mitochondrial uncoupling, placing NMNAT2 loss upstream of SARM1 activation in mitochondrial-stress-induced Wallerian degeneration.\",\n      \"method\": \"Mitochondrial uncoupler treatment of mouse SCG neurons, NMNAT2 protein/transport measurement, NMN/NAD ratio assay, WldS expression and Sarm1-KO rescue, Pink1 fly model lifespan assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — metabolite profiling, transport assay, genetic rescue with WldS and Sarm1 deletion, cross-species validation in Drosophila\",\n      \"pmids\": [\"31740269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NMNAT2 maintains NAD redox potential in distal axons to support vesicular glycolysis providing on-board ATP for fast axonal transport. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. SARM1 reduction (not NAD+ supplementation) rescues mitochondrial function in NMNAT2 KO neurons, indicating SARM1 mediates the mitochondrial dysfunction downstream of NMNAT2 loss.\",\n      \"method\": \"NMNAT2 conditional KO mouse model, live axonal transport imaging, glycolysis/OXPHOS metabolic assays, NAD+ sensor imaging, antisense oligonucleotides for SARM1 knockdown, Seahorse metabolic flux\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, metabolic flux, genetic and pharmacological rescue), in vivo and in vitro consistency\",\n      \"pmids\": [\"38282024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Deletion of central ISTID sequences (including the palmitoylation domain) abolishes vesicle association, increases NMNAT2 protein stability in peripheral axons in vivo, and enhances axon protective capacity both in mouse and Drosophila, establishing that ISTID-mediated membrane tethering controls NMNAT2 turnover in vivo.\",\n      \"method\": \"Transgenic fluorescently tagged NMNAT2 with ISTID deletions in mouse sciatic nerve, Drosophila ORN axon protection assay in vivo, protein stability measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse and Drosophila models with domain deletion, single lab, consistent with in vitro palmitoylation data\",\n      \"pmids\": [\"23995269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMNAT2 transcription is directly regulated by CREB via two functional CRE sites in the nmnat2 promoter. In tauopathy (rTg4510) mice, reduced pCREB binding to these CRE sites precedes neurodegeneration and correlates with decreased NMNAT2 mRNA and protein. AAV-mediated NMNAT2 overexpression reduces neurodegeneration in rTg4510 hippocampi.\",\n      \"method\": \"CRE site identification, EMSA/ChIP for pCREB binding, rTg4510 mouse model, AAV-mediated NMNAT2 overexpression, histological neurodegeneration quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP for direct CRE binding, in vivo AAV rescue, single lab\",\n      \"pmids\": [\"22027994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NMNAT2 activates protein phosphatase 2A (PP2A), reducing tau phosphorylation at multiple AD-associated sites. Overexpression of NMNAT2 activates PP2A with attenuation of tau phosphorylation; NMNAT2 shRNA knockdown inhibits PP2A and causes tau hyperphosphorylation. PP2A inhibition abolishes NMNAT2-induced tau dephosphorylation.\",\n      \"method\": \"HEK293/tau cell overexpression and shRNA knockdown, PP2A activity assay, okadaic acid (PP2A inhibitor) epistasis, tau phosphorylation western blot at multiple sites\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based gain/loss-of-function with PP2A inhibitor epistasis, single lab, no direct physical interaction demonstrated\",\n      \"pmids\": [\"23579329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NMNAT2 overexpression blocks angiotensin II-induced cardiac hypertrophy in neonatal rat cardiomyocytes through activation of SIRT6 by maintaining intracellular NAD levels. A catalytically inactive NMNAT2 mutant does not block hypertrophy, demonstrating dependence on enzymatic NAD synthesis activity.\",\n      \"method\": \"Neonatal rat cardiomyocyte overexpression with catalytically inactive mutant, Ang II hypertrophy model, SIRT6 activity measurement, NAD level assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant used to establish enzymatic dependence, SIRT6 activity measured, single lab\",\n      \"pmids\": [\"22449973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT3 interacts with and deacetylates NMNAT2, and this interaction regulates NMNAT2 NAD+ synthesis activity. Downregulation of SIRT3 inhibits NMNAT2 deacetylation and reduces NAD+ synthesis activity in NSCLC cells.\",\n      \"method\": \"Yeast two-hybrid screen, Co-IP in vitro and in vivo, deacetylation assay, NAD+ synthesis activity measurement — NOTE: This paper (PMID:24042441) was subsequently retracted (PMID:37026521) due to data integrity concerns\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — paper retracted; data integrity compromised; findings cannot be relied upon\",\n      \"pmids\": [\"24042441\", \"37026521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMNAT2 expression is induced upon DNA damage in a p53-dependent manner. Two functional p53 binding sites within the human NMNAT2 gene were identified and validated. NMNAT2 knockdown reduces cellular NAD+ levels and protects cells from p53-dependent cell death upon DNA damage, indicating NMNAT2 mediates p53-dependent metabolic and cell-death signaling.\",\n      \"method\": \"p53 binding site identification and reporter assay, DNA damage treatment with p53-dependent induction, NMNAT2 knockdown with NAD+ measurement, cell death assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional p53 binding sites validated in reporter assay, knockdown with NAD+ and cell viability readouts, single lab\",\n      \"pmids\": [\"24552824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NMNAT2-deficient oocytes have disturbed meiotic apparatus assembly and elevated ROS. SIRT1 activation or overexpression partially prevents meiotic defects caused by NMNAT2 depletion, establishing a NMNAT2-NAD+-SIRT1 pathway controlling redox homeostasis during oocyte meiotic maturation.\",\n      \"method\": \"NMNAT2-specific depletion in mouse oocytes, spindle/chromosome assembly assay, ROS measurement, SIRT1 genetic and pharmacological rescue\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific depletion with defined cellular phenotype, genetic epistasis via SIRT1 rescue, single lab\",\n      \"pmids\": [\"30909324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chronically low NMNAT2 levels lead to sub-lethal SARM1 activation in morphologically intact axons, characterized by NAD(P) depletion and compromised neurite outgrowth, without overt axon degeneration. Low NMNAT2 reverses the NAD-enhancing effect of nicotinamide riboside in axons in a SARM1-dependent manner.\",\n      \"method\": \"Compound heterozygote NMNAT2 mice, SCG primary cultures, NAD(P) measurement, neurite outgrowth assay, SARM1 genetic deletion epistasis, nicotinamide riboside treatment\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with SARM1 deletion, multiple metabolite and morphological readouts, single lab\",\n      \"pmids\": [\"39352636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMNAT2 suppresses amyloid-beta production and upregulates alpha-secretase ADAM10 via an AMPK-dependent mechanism. Overexpression of NMNAT2 increases the NAD+/NADH ratio, activates AMPK, and increases ADAM10 mRNA and activity; this effect is abolished by the AMPK antagonist Compound C.\",\n      \"method\": \"N2a/APPswe cell overexpression, AMPK inhibitor (Compound C) epistasis, ADAM10 activity assay, Abeta measurement, NAD+/NADH ratio\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-based overexpression with pharmacological epistasis, single lab, no direct NMNAT2-AMPK interaction demonstrated\",\n      \"pmids\": [\"34644262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In DRG neurons, the Raf-MEK-ERK cascade upregulates Nmnat2 via ERK phosphorylation-dependent transcription, maintaining axon survival. MEK inhibition decreases Nmnat2 expression and induces axon degeneration in DRG neurons, rescued by Nmnat2 overexpression. Cortical and spinal neurons maintain Nmnat2 via CREB (independent of MEK-ERK), demonstrating neuron subtype-specific transcriptional regulation of Nmnat2.\",\n      \"method\": \"MEK inhibitor treatment of DRG/cortical/spinal neurons, Nmnat2 mRNA/protein quantification, ERK phosphorylation assays, Nmnat2 overexpression rescue, axon degeneration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ERK-dependent transcription with rescue by Nmnat2 overexpression, neuron-type comparison, single lab\",\n      \"pmids\": [\"41619208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4, ATF6, SOX11, and HSF1 are required for NMNAT2 transcription in SH-SY5Y cells; specific genomic regulatory regions identified by 4C-seq (chromosome conformation capture) interact with the NMNAT2 promoter in undifferentiated versus neuron-like states. CRISPR-Cas9 deletion of two regulatory regions confirmed their requirement for NMNAT2 transcription.\",\n      \"method\": \"4C-seq, CRISPR-Cas9 deletion of regulatory regions, luciferase reporter assays, transcription factor knockdown/overexpression in SH-SY5Y cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR validation of regulatory regions, TF requirement confirmed functionally, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41241829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human NMNAT2 missense mutations (compound heterozygous in FADS patients; homozygous T94M in polyneuropathy/erythromelalgia patients) cause partial or complete loss of function in both NAD+ synthesis and chaperone functions. The T94M substitution confers reduced ability to support axon survival in mouse primary neuron cultures and has altered enzymatic properties, establishing NMNAT2 as the causative gene in these human axonal disorders.\",\n      \"method\": \"Patient exome sequencing, mouse primary neuron axon survival assay with mutant overexpression, in vitro NAD+ synthesis assay, protein stability assay, chaperone function assay\",\n      \"journal\": \"Experimental neurology / Experimental neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple functional assays (enzymatic, chaperone, axon survival) on patient-derived variants, two independent patient studies with consistent findings\",\n      \"pmids\": [\"31136762\", \"31132363\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NMNAT2 is a labile, palmitoylated NAD+-synthesizing enzyme that is constitutively transported anterogradely on trans-Golgi-derived vesicles into axons; its rapid turnover (controlled by an atypical SCF ubiquitin ligase complex containing PAM/MYCBP2–FBXO45–SKP1 and a separate SCFFBXO21 complex that ubiquitinates K155) means that axon survival depends on continuous resupply, and when NMNAT2 falls below a threshold—due to injury, MAPK-accelerated degradation, or reduced transcription (regulated by CREB, ERK-dependent pathways, ATF4/ATF6/SOX11/HSF1)—NMN accumulates and allosterically activates the NAD+ hydrolase SARM1, triggering axon degeneration; additionally, NMNAT2 functions as an HSP90-dependent molecular chaperone (via a C-terminal ATP site) to refold misfolded proteins, and regulates downstream effectors including SIRT6, PP2A, and AMPK to protect neurons from hypertrophy, tau phosphorylation, and amyloidogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NMNAT2 is a labile NAD+-synthesizing enzyme that functions as an essential axon survival and maintenance factor, constitutively replenished by fast anterograde axonal transport such that its continuous resupply is rate-limiting for axon integrity [#0, #10]. It is trafficked bidirectionally on trans-Golgi network/vesicle-associated carriers, and palmitoylation of a double-cysteine motif within its isoform-specific targeting and interaction domain (ISTID) drives stable membrane association and vesicular transport while simultaneously controlling its rapid turnover; disrupting membrane tethering stabilizes the protein and enhances its axon-protective capacity [#1, #14]. Palmitoylation is dynamically set by zDHHC17/HIP14 and the thioesterases APT1/APT2 on a timescale matched to NMNAT2's short half-life [#2]. Its instability is enforced by proteasomal degradation through an atypical PHR/SCF-type ubiquitin ligase comprising MYCBP2(PAM)\\u2013FBXO45\\u2013SKP1 and a distinct SCF^FBXO21 (SKP1\\u2013CUL1\\u2013RBX1) complex that ubiquitinates lysine K155 within the ISTID; loss of either degradation route elevates NMNAT2 and protects injured axons [#7, #8, #9]. When NMNAT2 falls below threshold\\u2014via injury, MAPK-accelerated turnover, mitochondrial stress, or reduced transcription\\u2014accumulating NMN drives activation of the pro-degenerative NAD+ hydrolase SARM1, and axon degeneration downstream of NMNAT2 loss genetically requires SARM1 [#3, #6, #11, #12]. Mechanistically, NMNAT2-maintained NAD redox potential supports vesicular glycolysis that powers fast axonal transport in distal axons [#13]. NMNAT2 is required in vivo for developmental axon extension, and its transcription is governed in a neuron-subtype-specific manner by CREB, Raf-MEK-ERK signaling, and the factors ATF4/ATF6/SOX11/HSF1 [#4, #15, #23, #24]. Beyond its enzymatic role, NMNAT2 acts as an HSP90-dependent refoldase via a unique C-terminal ATP site, providing an enzyme-independent chaperone activity against proteotoxic stress [#5]. Loss-of-function NMNAT2 mutations cause human axonal disorders including fetal akinesia deformation sequence and a polyneuropathy/erythromelalgia syndrome [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that NMNAT2's axon-protective capacity depends on its NAD-synthesizing catalytic activity, framing the protein as an enzyme acting within neurons rather than merely a structural factor.\",\n      \"evidence\": \"Active-site mutagenesis with NAD synthesis and axon degeneration readouts in SCG primary cultures\",\n      \"pmids\": [\"19778564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address endogenous turnover or transport\", \"Mechanism linking NAD synthesis to protection not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified endogenous NMNAT2 as an intrinsically labile axon survival factor whose continuous transport-dependent resupply is rate-limiting, explaining why axons degenerate when supply is interrupted.\",\n      \"evidence\": \"Specific Nmnat2 depletion, live neurite imaging, proteasome inhibition and half-life measurements in primary neurons\",\n      \"pmids\": [\"20126265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation machinery not identified\", \"Downstream degeneration effector unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how NMNAT2 is delivered to and turned over in axons, showing palmitoylation of an ISTID double-cysteine motif controls vesicular transport and instability.\",\n      \"evidence\": \"Dual-colour axonal transport imaging, palmitoylation mutagenesis, and transected neurite protection assays in SCG neurons; in vivo ISTID-deletion transgenics in mouse and Drosophila\",\n      \"pmids\": [\"23610559\", \"23995269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes setting palmitoylation not yet identified\", \"Link between membrane tethering and degradation machinery undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated an in vivo requirement for NMNAT2 in developmental axon extension, distinguishing this from dying-back degeneration and showing WldS can substitute.\",\n      \"evidence\": \"Nmnat2 gene-trap mice, embryonic histology, PNS/CNS cultures, WldS genetic rescue\",\n      \"pmids\": [\"23946398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve degenerative effector downstream of NMNAT2 loss\", \"Metabolite basis of rescue not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the palmitoylation/depalmitoylation cycle (zDHHC17 vs APT1/APT2) that dynamically regulates NMNAT2 membrane association on a timescale matching its half-life.\",\n      \"evidence\": \"Enzymatic identification of palmitoyltransferases and thioesterases, palmitoylation and half-life assays\",\n      \"pmids\": [\"25271157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of specific zDHHC/APT enzymes not tested\", \"Coupling to ubiquitin-proteasome pathway unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SARM1 genetically downstream of NMNAT2 loss and implicated NMN accumulation as the pro-degenerative signal, defining the core axon-destruction axis.\",\n      \"evidence\": \"NMNAT2/SARM1 double-knockout epistasis, metabolite profiling, NAMPT inhibition rescue, axon outgrowth assays\",\n      \"pmids\": [\"25818290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between NMN and SARM1 not shown here\", \"Threshold dynamics not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an enzyme-independent chaperone (refoldase) function of NMNAT2 via a C-terminal ATP site and HSP90 partnership, establishing dual context-dependent functions.\",\n      \"evidence\": \"NMNAT2-HSP90 Co-IP, in vitro refoldase assay, C-terminal ATP-site mutagenesis, cortical neuron stress assays\",\n      \"pmids\": [\"27254664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates of the chaperone activity not identified\", \"Relative contribution in vivo unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified SKP1 as a core component of an atypical SCF-type ligase controlling axonal NMNAT2 levels, with depletion protecting axons upstream of NMNAT2.\",\n      \"evidence\": \"Skp1a knockdown, in vitro and in vivo (optic nerve) degeneration assays, epistasis with Nmnat2 knockdown, ATP measurement\",\n      \"pmids\": [\"27732853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ligase composition not resolved in this study\", \"Ubiquitination site not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterized the atypical PHR (MYCBP2/PAM)\\u2013FBXO45\\u2013SKP1 SCF-like ligase that polyubiquitinates NMNAT2 for degradation, identifying a specific degradation machinery.\",\n      \"evidence\": \"Complex Co-IP, in vitro ubiquitination and proteasome degradation assays, domain mapping\",\n      \"pmids\": [\"29997255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo neuronal requirement not established here\", \"Target lysine residues not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Positioned MAPK signaling upstream of SARM1 by showing it accelerates NMNAT2 turnover, integrating injury signaling into the NMNAT2-SARM1 axis.\",\n      \"evidence\": \"MAPK inhibition/activation, NMNAT2 half-life measurement, SARM1 epistasis in mammalian and Drosophila neurons\",\n      \"pmids\": [\"28095293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MAPK substrate in the turnover pathway not identified\", \"Connection to specific E3 ligase undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed NMN accumulation, not NAD deficit alone, as the pro-degenerative trigger by rescuing NMNAT2-deficient phenotypes with NMN-consuming deamidase.\",\n      \"evidence\": \"Transgenic NMN deamidase in zebrafish and mice, NMNAT2 KO rescue, NMN measurement\",\n      \"pmids\": [\"28262487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address contributions of NAD in other contexts\", \"SARM1 activation mechanism by NMN not biochemically shown here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked mitochondrial stress to Wallerian-type degeneration through NMNAT2 depletion upstream of SARM1, broadening the upstream triggers of the axis.\",\n      \"evidence\": \"Mitochondrial uncoupler treatment of SCG neurons, NMNAT2/transport and NMN/NAD measurement, WldS and Sarm1-KO rescue, Pink1 fly model\",\n      \"pmids\": [\"31740269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism reducing NMNAT2 synthesis/transport not fully defined\", \"Crosstalk with proteostatic degradation unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Explained how NMNAT2-maintained NAD redox supports vesicular glycolysis to power fast axonal transport, providing a metabolic mechanism for its maintenance role.\",\n      \"evidence\": \"NMNAT2 conditional KO, live transport imaging, NAD+ sensor, Seahorse flux, SARM1 ASO knockdown\",\n      \"pmids\": [\"38282024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycolytic machinery on vesicles not fully defined\", \"Quantitative link between NAD level and transport speed incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed chronically low NMNAT2 causes sub-lethal SARM1 activation in intact axons, defining a threshold-dependent pre-degenerative state relevant to disease.\",\n      \"evidence\": \"Compound heterozygote NMNAT2 mice, NAD(P) and neurite outgrowth assays, SARM1 deletion epistasis, nicotinamide riboside treatment\",\n      \"pmids\": [\"39352636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Long-term consequences of sub-lethal activation not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SCF^FBXO21 as a second ubiquitin ligase targeting NMNAT2 at K155 within the ISTID, mapping a defined degron and confirming in vivo relevance.\",\n      \"evidence\": \"Co-IP, in vitro/in vivo ubiquitination, K155R mutagenesis, FBXO21 KO mouse sciatic nerve injury\",\n      \"pmids\": [\"41026098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution versus PHR/FBXO45 ligase unresolved\", \"Regulation of FBXO21 activity unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a multi-factor transcriptional control of NMNAT2 (ATF4/ATF6/SOX11/HSF1) acting through specific chromatin-looping regulatory regions, refining how NMNAT2 levels are set.\",\n      \"evidence\": \"4C-seq, CRISPR deletion of regulatory regions, luciferase reporters, TF perturbation in SH-SY5Y cells\",\n      \"pmids\": [\"41241829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo neuronal relevance not tested\", \"Integration with CREB/ERK inputs unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated neuron-subtype-specific transcriptional regulation, with Raf-MEK-ERK driving Nmnat2 in DRG neurons while CREB operates in cortical/spinal neurons.\",\n      \"evidence\": \"MEK inhibition, ERK phosphorylation and Nmnat2 mRNA/protein assays, Nmnat2 overexpression rescue across neuron types\",\n      \"pmids\": [\"41619208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factor mediating ERK input not pinned\", \"Cross-talk with degradation control unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple degradation, palmitoylation, and transcriptional inputs are integrated to set the NMNAT2 threshold that gates SARM1 activation in different neuron types and disease states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of NMNAT2 supply-versus-degradation balance\", \"Relative weighting of PHR/FBXO45 vs SCF^FBXO21 ligases in vivo unknown\", \"Physiological chaperone substrates and their disease relevance undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10, 0, 17]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 13, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 9, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"MYCBP2(PAM)\\u2013FBXO45\\u2013SKP1 SCF-like ligase\",\n      \"SCF^FBXO21 (SKP1\\u2013CUL1\\u2013RBX1)\",\n      \"NMNAT2\\u2013HSP90 chaperone complex\"\n    ],\n    \"partners\": [\n      \"SARM1\",\n      \"HSP90\",\n      \"MYCBP2\",\n      \"FBXO45\",\n      \"SKP1\",\n      \"FBXO21\",\n      \"ZDHHC17\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}