Affinage

NMNAT2

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 · UniProt Q9BZQ4

Length
307 aa
Mass
34.4 kDa
Annotated
2026-06-10
55 papers in source corpus 28 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2009 High

    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

    PMID:19778564

    Open questions at the time
    • Did not address endogenous turnover or transport
    • Mechanism linking NAD synthesis to protection not yet defined
  2. 2010 High

    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

    PMID:20126265

    Open questions at the time
    • Degradation machinery not identified
    • Downstream degeneration effector unknown
  3. 2013 High

    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

    PMID:23610559 PMID:23995269

    Open questions at the time
    • Enzymes setting palmitoylation not yet identified
    • Link between membrane tethering and degradation machinery undefined
  4. 2013 High

    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

    PMID:23946398

    Open questions at the time
    • Did not resolve degenerative effector downstream of NMNAT2 loss
    • Metabolite basis of rescue not established
  5. 2014 High

    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

    PMID:25271157

    Open questions at the time
    • In vivo relevance of specific zDHHC/APT enzymes not tested
    • Coupling to ubiquitin-proteasome pathway unresolved
  6. 2015 High

    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

    PMID:25818290

    Open questions at the time
    • Direct biochemical link between NMN and SARM1 not shown here
    • Threshold dynamics not quantified
  7. 2016 High

    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

    PMID:27254664

    Open questions at the time
    • Physiological substrates of the chaperone activity not identified
    • Relative contribution in vivo unquantified
  8. 2016 High

    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

    PMID:27732853

    Open questions at the time
    • Full ligase composition not resolved in this study
    • Ubiquitination site not mapped
  9. 2017 High

    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

    PMID:29997255

    Open questions at the time
    • In vivo neuronal requirement not established here
    • Target lysine residues not mapped
  10. 2017 High

    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

    PMID:28095293

    Open questions at the time
    • Direct MAPK substrate in the turnover pathway not identified
    • Connection to specific E3 ligase undefined
  11. 2017 High

    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

    PMID:28262487

    Open questions at the time
    • Does not address contributions of NAD in other contexts
    • SARM1 activation mechanism by NMN not biochemically shown here
  12. 2019 High

    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

    PMID:31740269

    Open questions at the time
    • Mechanism reducing NMNAT2 synthesis/transport not fully defined
    • Crosstalk with proteostatic degradation unexplored
  13. 2024 High

    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

    PMID:38282024

    Open questions at the time
    • Glycolytic machinery on vesicles not fully defined
    • Quantitative link between NAD level and transport speed incomplete
  14. 2024 Medium

    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

    PMID:39352636

    Open questions at the time
    • Long-term consequences of sub-lethal activation not established
    • Single lab
  15. 2025 High

    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

    PMID:41026098

    Open questions at the time
    • Relative contribution versus PHR/FBXO45 ligase unresolved
    • Regulation of FBXO21 activity unknown
  16. 2025 Medium

    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

    PMID:41241829

    Open questions at the time
    • In vivo neuronal relevance not tested
    • Integration with CREB/ERK inputs unresolved
  17. 2026 Medium

    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

    PMID:41619208

    Open questions at the time
    • Direct transcription factor mediating ERK input not pinned
    • Cross-talk with degradation control unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0044183 protein folding chaperone 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 1
Partners
FBXO21FBXO45HSP90MYCBP2SARM1SKP1ZDHHC17
Complex memberships
MYCBP2(PAM)–FBXO45–SKP1 SCF-like ligaseNMNAT2–HSP90 chaperone complexSCF^FBXO21 (SKP1–CUL1–RBX1)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Primary neuron culture with specific Nmnat2 depletion, live neurite imaging, proteasome inhibitor treatment, half-life measurements across Nmnat isoforms PLoS biology High 20126265
2013 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. Dual-colour live-cell imaging of axonal transport in SCG neurons, palmitoylation mutagenesis, co-migration analysis with organelle markers, transected neurite protection assays PLoS biology High 23610559
2014 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. Biochemical identification of palmitoyltransferases and thioesterases acting on NMNAT2, palmitoylation assays, subcellular localization studies, half-life measurements The Journal of biological chemistry High 25271157
2015 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. Genetic epistasis in NMNAT2/SARM1 double-knockout mice, metabolite measurements in injured axons, NAMPT inhibitor treatment, axon outgrowth assays Cell reports High 25818290
2013 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. Nmnat2 gene-trap mouse generation, embryonic histology, PNS/CNS neuronal cultures, WldS genetic rescue The Journal of neuroscience High 23946398
2016 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. Co-immunoprecipitation of NMNAT2-HSP90 complex, in vitro refoldase assay, C-terminal ATP site mutagenesis, cortical neuron deletion/stress assays PLoS biology High 27254664
2017 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. Cultured mammalian neurons and Drosophila motor neurons, MAPK pathway inhibition/activation, NMNAT2 protein half-life measurements, SARM1 epistasis experiments eLife High 28095293
2018 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. Biochemical complex characterization, Co-IP, in vitro ubiquitination assay, proteasome degradation assay, domain mapping The Journal of biological chemistry High 29997255
2016 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. 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 Cell reports High 27732853
2025 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. Co-IP for complex identification, in vitro and in vivo ubiquitination assay, site-directed mutagenesis (K155R), FBXO21 knockout mouse sciatic nerve injury model The Journal of cell biology High 41026098
2009 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. SCG primary culture axon degeneration assay, active-site mutagenesis, NAD synthesis activity measurement Neurochemistry international High 19778564
2017 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. Transgenic NMN deamidase expression in zebrafish and mice, NMNAT2 KO rescue experiment, NMN measurement in sciatic nerve Current biology High 28262487
2019 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. 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 Neurobiology of disease High 31740269
2024 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. NMNAT2 conditional KO mouse model, live axonal transport imaging, glycolysis/OXPHOS metabolic assays, NAD+ sensor imaging, antisense oligonucleotides for SARM1 knockdown, Seahorse metabolic flux Molecular neurodegeneration High 38282024
2013 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. Transgenic fluorescently tagged NMNAT2 with ISTID deletions in mouse sciatic nerve, Drosophila ORN axon protection assay in vivo, protein stability measurement Scientific reports Medium 23995269
2011 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. CRE site identification, EMSA/ChIP for pCREB binding, rTg4510 mouse model, AAV-mediated NMNAT2 overexpression, histological neurodegeneration quantification Human molecular genetics Medium 22027994
2013 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. HEK293/tau cell overexpression and shRNA knockdown, PP2A activity assay, okadaic acid (PP2A inhibitor) epistasis, tau phosphorylation western blot at multiple sites Journal of Alzheimer's disease Medium 23579329
2012 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. Neonatal rat cardiomyocyte overexpression with catalytically inactive mutant, Ang II hypertrophy model, SIRT6 activity measurement, NAD level assay FEBS letters Medium 22449973
2013 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. 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 International journal of oncology Low 24042441 37026521
2014 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. p53 binding site identification and reporter assay, DNA damage treatment with p53-dependent induction, NMNAT2 knockdown with NAD+ measurement, cell death assay Cell cycle Medium 24552824
2019 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. NMNAT2-specific depletion in mouse oocytes, spindle/chromosome assembly assay, ROS measurement, SIRT1 genetic and pharmacological rescue Aging cell Medium 30909324
2024 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. Compound heterozygote NMNAT2 mice, SCG primary cultures, NAD(P) measurement, neurite outgrowth assay, SARM1 genetic deletion epistasis, nicotinamide riboside treatment Molecular neurobiology Medium 39352636
2021 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. N2a/APPswe cell overexpression, AMPK inhibitor (Compound C) epistasis, ADAM10 activity assay, Abeta measurement, NAD+/NADH ratio Aging Low 34644262
2026 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. MEK inhibitor treatment of DRG/cortical/spinal neurons, Nmnat2 mRNA/protein quantification, ERK phosphorylation assays, Nmnat2 overexpression rescue, axon degeneration assays Cell reports Medium 41619208
2025 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. 4C-seq, CRISPR-Cas9 deletion of regulatory regions, luciferase reporter assays, transcription factor knockdown/overexpression in SH-SY5Y cells The FEBS journal Medium 41241829
2019 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. Patient exome sequencing, mouse primary neuron axon survival assay with mutant overexpression, in vitro NAD+ synthesis assay, protein stability assay, chaperone function assay Experimental neurology / Experimental neurology High 31132363 31136762

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS biology 411 20126265
2015 Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell reports 165 25818290
2017 MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. eLife 133 28095293
2016 NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. PLoS biology 109 27254664
2013 Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS biology 109 23610559
2013 Rescue of peripheral and CNS axon defects in mice lacking NMNAT2. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 23946398
2019 Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration. Neurobiology of disease 100 31740269
2011 CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Human molecular genetics 97 22027994
2017 NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency In Vivo. Current biology : CB 85 28262487
2009 Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity. Neurochemistry international 84 19778564
2012 Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6. FEBS letters 80 22449973
2019 NMNAT2-mediated NAD+ generation is essential for quality control of aged oocytes. Aging cell 71 30909324
2012 Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo. PloS one 65 23082226
2013 SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. International journal of oncology 58 24042441
2022 NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function. Molecular therapy : the journal of the American Society of Gene Therapy 56 35114390
2019 Low levels of NMNAT2 compromise axon development and survival. Human molecular genetics 48 30304512
2019 Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence. Experimental neurology 46 31136762
2019 Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia. Experimental neurology 45 31132363
2018 PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2. The Journal of biological chemistry 41 29997255
2016 An Atypical SCF-like Ubiquitin Ligase Complex Promotes Wallerian Degeneration through Regulation of Axonal Nmnat2. Cell reports 41 27732853
2013 Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo. Scientific reports 41 23995269
2017 A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. Journal of human genetics 40 28855716
2017 Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Scientific reports 37 28266613
2010 Overexpression of Wld(S) or Nmnat2 in mauthner cells by single-cell electroporation delays axon degeneration in live zebrafish. Journal of neuroscience research 37 20857515
2013 Nmnat2 attenuates Tau phosphorylation through activation of PP2A. Journal of Alzheimer's disease : JAD 36 23579329
2021 EGCG inhibits pressure overload-induced cardiac hypertrophy via the PSMB5/Nmnat2/SIRT6-dependent signalling pathways. Acta physiologica (Oxford, England) 35 33315278
2014 The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target. Cell cycle (Georgetown, Tex.) 34 24552824
2014 Identification of palmitoyltransferase and thioesterase enzymes that control the subcellular localization of axon survival factor nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). The Journal of biological chemistry 32 25271157
2024 NMNAT2 is a druggable target to drive neuronal NAD production. Nature communications 31 39048544
2018 Downregulated SIRT6 and upregulated NMNAT2 are associated with the presence, depth and stage of colorectal cancer. Oncology letters 31 30333863
2023 Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6-OHDA-lesioned rat model of Parkinson's disease. Journal of neuroinflammation 27 37208728
2013 Axonal trafficking of NMNAT2 and its roles in axon growth and survival in vivo. Bioarchitecture 26 24284888
2024 NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport. Molecular neurodegeneration 21 38282024
2016 Impact of Genetic Reduction of NMNAT2 on Chemotherapy-Induced Losses in Cell Viability In Vitro and Peripheral Neuropathy In Vivo. PloS one 21 26808812
2018 Increased ROS Level in Spinal Cord of Wobbler Mice due to Nmnat2 Downregulation. Molecular neurobiology 19 29549647
2021 An NAD+/NMN balancing act by SARM1 and NMNAT2 controls axonal degeneration. Neuron 17 33831359
2022 NMNAT2: An important metabolic enzyme affecting the disease progression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 36528916
2021 Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner. Aging 16 34644262
2024 The Role of NMNAT2/SARM1 in Neuropathy Development. Biology 8 38275737
2024 Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons. Molecular neurobiology 6 39352636
2016 Two for the Price of One: A Neuroprotective Chaperone Kit within NAD Synthase Protein NMNAT2. PLoS biology 6 27454736
2021 Neuronal NMNAT2 Overexpression Does Not Achieve Significant Neuroprotection in Experimental Autoimmune Encephalomyelitis/Optic Neuritis. Frontiers in cellular neuroscience 5 34707482
2020 Upregulated Nmnat2 causes neuronal death and increases seizure susceptibility in temporal lobe epilepsy. Brain research bulletin 5 33248200
2023 Downregulation of SIRT6 and NMNAT2 is associated with proliferative diabetic retinopathy. Molecular vision 4 38222451
2016 Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant: a case report. Translational neurodegeneration 4 28035283
2013 Lack of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2): consequences for mouse bladder development and function. Neurourology and urodynamics 4 23371862
2025 SCFFBXO21-mediated ubiquitination and degradation of NMNAT2 regulates axon survival in nerve injury. The Journal of cell biology 1 41026098
2025 Transcriptional regulation of human NMNAT2: insights from 3D genome sequencing and bioinformatics. The FEBS journal 1 41241829
2023 NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport. Research square 1 37292715
2022 Loss-of-function approach using mouse retinal explants showed pivotal roles of Nmnat2 in early and middle stages of retinal development. Molecular biology of the cell 1 36322391
2026 A neuron subtype-specific role of MEK-ERK signaling in axon survival via transcriptional regulation of Nmnat2. Cell reports 0 41619208
2026 DLK, NMNAT2, and SARM1: Judge, Jury, and Executioner in Axon Degeneration. Annual review of biochemistry 0 41861244
2026 NMNAT2-SARM1 Axis Drives Redox Failure and Disrupts APP Processing in Neurons. bioRxiv : the preprint server for biology 0 42079138
2024 "Transcriptional Regulation of human NMNAT2: Insights from 3D Genome Sequencing and Bioinformatics". bioRxiv : the preprint server for biology 0 39574670
2023 [Retracted] SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non‑small cell lung cancer cells through deacetylation of NMNAT2. International journal of oncology 0 37026521

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