Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons

We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related WldS protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.

• Publication year

  2010

• Venue

  PLoS Biology

• Publication date

  2010-01-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pbio.1000300PMID 20126265PMCID 2811159
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity.

  2010influential reference
• WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration

  2009cited by this paper
• A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins.

  2009cited by this paper
• Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration

  2009influential reference
• Nicotinamide Mononucleotide Adenylyl Transferase-Mediated Axonal Protection Requires Enzymatic Activity But Not Increased Levels of Neuronal Nicotinamide Adenine Dinucleotide

  2009influential reference
• A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration

  2009cited by this paper
• WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice

  2009cited by this paper
• Transgenic Mice Expressing the Nmnat1 Protein Manifest Robust Delay in Axonal Degeneration In Vivo

  2009cited by this paper
• Non-Nuclear WldS Determines Its Neuroprotective Efficacy for Axons and Synapses In Vivo

  2009cited by this paper
• Role of axonal transport in neurodegenerative diseases.

  2008cited by this paper
• In vivo imaging of axonal transport using MRI: aging and Alzheimer’s disease

  2008cited by this paper
• NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

  2008influential reference
• Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: activation of SIRT2, an NAD-dependent tubulin deacetylase.

  2007cited by this paper
• NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration

  2007cited by this paper
• Rate of neurite outgrowth in sympathetic neurons is highly resistant to suppression of protein synthesis: role of protein degradation/synthesis coupling.

  2007cited by this paper
• Stimulation of Nicotinamide Adenine Dinucleotide Biosynthetic Pathways Delays Axonal Degeneration after Axotomy

  2006influential reference
• Drosophila NMNAT Maintains Neural Integrity Independent of Its NAD Synthesis Activity

  2006cited by this paper
• Axonal transport and neurodegenerative disease.

  2006cited by this paper
• The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse.

  2005cited by this paper
• Regulation of Wallerian degeneration and nerve growth factor withdrawal-induced pruning of axons of sympathetic neurons by the proteasome and the MEK/Erk pathway.

  2005cited by this paper
• Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms*

  2005cited by this paper
• A local mechanism mediates NAD-dependent protection of axon degeneration

  2005cited by this paper
• A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses

  2005cited by this paper
• The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves

  2005cited by this paper
• In vivo imaging of axonal degeneration and regeneration in the injured spinal cord

  2005cited by this paper
• Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration

  2004influential reference
• Quantitative and qualitative analysis of Wallerian degeneration using restricted axonal labelling in YFP-H mice

  2004cited by this paper
• Proteasome inhibition arrests neurite outgrowth and causes “dying‐back” degeneration in primary culture

  2003cited by this paper
• Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease.

  2003cited by this paper
• Mutant dynactin in motor neuron disease

  2003cited by this paper
• Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration.

  2003influential reference
• Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport

  2003cited by this paper
• Structural Characterization of a Human Cytosolic NMN/NaMN Adenylyltransferase and Implication in Human NAD Biosynthesis* 210

  2003influential reference
• The proapoptotic proteins Bax and Bak are not involved in Wallerian degeneration

  2003cited by this paper
• A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).

  2002cited by this paper
• Identification of a novel human nicotinamide mononucleotide adenylyltransferase.

  2002influential reference
• Stable expression of calpain 3 from a muscle transgene in vivo: Immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation

  2002cited by this paper
• Wlds mice are resistant to paclitaxel (taxol) neuropathy

  2002cited by this paper
• Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.

  2001cited by this paper
• The gene for slow Wallerian degeneration (Wld(s)) is also protective against vincristine neuropathy.

  2001cited by this paper
• Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity.

  2001cited by this paper
• Molecular Cloning, Chromosomal Localization, Tissue mRNA Levels, Bacterial Expression, and Enzymatic Properties of Human NMN Adenylyltransferase*

  2001cited by this paper
• Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene

  2001cited by this paper
• Evidence That Wallerian Degeneration and Localized Axon Degeneration Induced by Local Neurotrophin Deprivation Do Not Involve Caspases

  2000cited by this paper
• A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse.

  2000cited by this paper
• A Ufd2 y D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (Wld S ) mouse

  2000cited by this paper
• Synthesis of β-Tubulin, Actin, and Other Proteins in Axons of Sympathetic Neurons in Compartmented Cultures

  1999cited by this paper
• Temperature Modulation Reveals Three Distinct Stages of Wallerian Degeneration

  1999cited by this paper
• Protein synthesis in pseudorabies virus-infected cells: decreased expression of protein kinase PKR, and effects of 2-aminopurine and adenine.

  1998cited by this paper
• Construction and Use of Compartmented Cultures

  1997cited by this paper
• Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons

  1996cited by this paper
• Neurites can remain viable after destruction of the neuronal soma by programmed cell death (apoptosis).

  1994cited by this paper
• Biochemical characterization of programmed cell death in NGF-deprived sympathetic neurons.

  1992cited by this paper
• Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve

  1989cited by this paper
• Compositional analysis of growing axons from rat sympathetic neurons

  1978cited by this paper
• Early course of Wallerian degeneration in myelinated fibres of the rat phrenic nerve.

  1977cited by this paper

• Combinatorial chemistry identifies additional compounds that selectively inhibit DLK-dependent retrograde signaling while minimally affecting other axonal roles of DLK

  2026cites this paper
• Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure–Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation

  2026cites this paper
• A neuron subtype-specific role of MEK-ERK signaling in axon survival via transcriptional regulation of Nmnat2.

  2026cites this paper
• Evaluation of Nicotinamide Riboside in Prevention of Small Nerve Fiber Axon Degeneration and Promotion of Nerve Regeneration.

  2026cites this paper
• Genetic Deletion of Sarm1 in Mouse Models of Three Neurological Diseases

  2025cites this paper
• Targeting SARM1: from inhibition for neuroprotection to activation for neuroablation.

  2025cites this paper
• Update on Nicotinamide and Its Application in the Management of Glaucoma

  2025cites this paper
• Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration

  2025influential citation
• NAD⁺ Reduction in Glutamatergic Neurons Induces Lipid Catabolism and Neuroinflammation in the Brain via SARM1

  2025cites this paper
• Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

  2025cites this paper
• Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin

  2025cites this paper
• A redox-dependent switch governing sensory axon degeneration and regeneration

  2025cites this paper
• A dNmnat-sensitized in vivo platform for unbiased discovery of regulators of neurodegeneration

  2025cites this paper
• SCFFBXO21-mediated ubiquitination and degradation of NMNAT2 regulates axon survival in nerve injury.

  2025cites this paper
• The Roles of Moonlighting Nicotinamide Mononucleotide Adenylyl Transferases in Cell Physiology

  2025cites this paper
• Nerve growth factor signaling tunes axon maintenance protein abundance and kinetics of Wallerian degeneration

  2025influential citation
• Nmnat2 deficiency in the arcuate nucleus or paraventricular nucleus induces Sarm1‐independent neuron loss and liraglutide‐reversible obesity

  2025cites this paper
• Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

  2025cites this paper
• Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies

  2025cites this paper
• SARM1: a key multifaceted component in immunoregulation, inflammation and neurodegeneration

  2025cites this paper
• High-fat diet triggers transcriptomic changes in the olfactory bulb

  2025cites this paper
• Programmed neurite degeneration in human central nervous system neurons driven by changes in NAD+ metabolism

  2025cites this paper
• Transcriptional regulation of human NMNAT2: insights from 3D genome sequencing and bioinformatics

  2025cites this paper
• Diverse cell types establish a pathogenic immune environment in peripheral neuropathy

  2025cites this paper
• Deletion of murine Sarm1 results in a microenvironment that delays peripheral nerve regeneration after injury.

  2025cites this paper
• NAD+ reduction in glutamatergic neurons triggers fatty acid catabolism and neuroinflammation in the brain, mitigated by SARM1 deletion

  2025cites this paper
• SARM1, the executioner of axon degeneration, is an ADP-ribosyl transferase and autoMARylation negatively regulates its activation

  2025cites this paper
• A single cell multi-omic analysis identifies molecular and gene-regulatory mechanisms dysregulated in the developing Down syndrome neocortex

  2025cites this paper
• NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease

  2025cites this paper
• Programmed axon degeneration: mechanism, inhibition and therapeutic potential

  2025influential citation
• Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

  2025cites this paper
• SARM1 is an essential component of neuronal Parthanatos

  2025cites this paper
• An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration

  2024cites this paper
• Gene therapy for glaucoma: Targeting key mechanisms

  2024cites this paper
• Local translatome sustains synaptic function in impaired Wallerian degeneration

  2024cites this paper
• Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells

  2024cites this paper
• Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide

  2024cites this paper
• Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons

  2024cites this paper
• Augustus Waller's foresight realized: SARM1 in peripheral neuropathies.

  2024cites this paper
• How does Nogo-A signalling influence mitochondrial function during multiple sclerosis pathogenesis?

  2024cites this paper
• Biological Functions and Therapeutic Potential of NAD+ Metabolism in Gynecological Cancers

  2024cites this paper
• Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

  2024cites this paper
• Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons

  2024cites this paper
• Programmed axon death: a promising target for treating retinal and optic nerve disorders

  2024cites this paper
• The Physiologic Basis of Molecular Therapeutics for Peripheral Nerve Injury: A Primer

  2024cites this paper
• Development and validation of an LC-MS/MS method for quantifying NAD+ and related metabolites in mice sciatic nerves and its application to a nerve injury animal model.

  2024cites this paper
• Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration

  2024cites this paper
• SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides

  2024cites this paper
• Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells.

  2024cites this paper
• The Role of NMNAT2/SARM1 in Neuropathy Development

  2024cites this paper
• Study of Axonal Injury and Degeneration in Drosophila.

  2024cites this paper
• Pyrrole adducts mediated mitochondrial dysfunction activates SARM1-dependent axon degeneration in 2,5-hexanedione-induced neuropathy.

  2024cites this paper
• The Mechanisms of Regulated Cell Death: Structural and Functional Proteomic Pathways Induced or Inhibited by a Specific Protein—A Narrative Review

  2024influential citation
• NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

  2024cites this paper
• Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

  2023cites this paper
• NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

  2023cites this paper
• STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes.

  2023cites this paper
• The Stathmin-2 membrane-targeting domain is required for axon protection and regulated degradation by DLK signaling

  2023cites this paper
• SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities

  2023influential citation
• Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve

  2023cites this paper
• Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence

  2023cites this paper
• SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice

  2023cites this paper
• Abnormal intraepidermal nerve fiber density in disease: A scoping review

  2023cites this paper
• Zn2+ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C

  2023cites this paper
• NMNAT1 and hereditary spastic paraplegia (HSP): expanding the phenotypic spectrum of NMNAT1 variants.

  2023cites this paper
• Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery.

  2023cites this paper
• NMN: The NAD Precursor at the Intersection Between Axon Degeneration and Anti-ageing Therapies.

  2023cites this paper
• Opposing roles of Fos, Raw, and SARM1 in the regulation of axonal degeneration and synaptic structure

  2023cites this paper
• Molecular aspects of optic nerve autophagy in glaucoma.

  2023cites this paper
• Roles of NAD+ in Health and Aging.

  2023cites this paper
• Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery

  2023influential citation
• The Molecular Mechanisms Involved in Axonal Degeneration and Retrograde Retinal Ganglion Cell Death

  2023cites this paper
• Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans

  2023cites this paper
• A phase transition reduces the threshold for nicotinamide mononucleotide-based activation of SARM1, an NAD(P) hydrolase, to physiologically relevant levels

  2023cites this paper
• Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging

  2023cites this paper
• Tau-mediated axonal degeneration is prevented by activation of the WldS pathway

  2023cites this paper
• A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration

  2023cites this paper
• Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

  2023cites this paper
• Regulation of Axon Degeneration after Injury and in Development by the Endogenous Calpain Inhibitor Calpastatin.

  2023cites this paper
• SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons

  2023cites this paper
• The use of Nicotinamide in Parkinson’s disease; A Possible path to the future. Review Article

  2023cites this paper
• NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve

  2023cites this paper
• NAD+, Axonal Maintenance, and Neurological Disease

  2023influential citation
• Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering.

  2023cites this paper
• Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease

  2023cites this paper
• NAD homeostasis maintained by NMNAT2 supports vesicular glycolysis and fuels fast axonal transport in distal axons of cortical glutamatergic neurons in mice

  2023cites this paper
• Of axons struggling making ends meet: Linking axonal bioenergetic failure to programmed axon degeneration.

  2022cites this paper
• Mitochondrial Reactive Oxygen Species Mediate Activation of TRPV1 and Calcium Entry Following Peripheral Sensory Axotomy

  2022cites this paper
• Human Nmnat1 Promotes Autophagic Clearance of Amyloid Plaques in a Drosophila Model of Alzheimer’s Disease

  2022cites this paper
• The Role of Axonal Transport in Glaucoma

  2022cites this paper
• Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

  2022cites this paper
• NAD+-dependent mechanism of pathological axon degeneration

  2022cites this paper
• An atypical ubiquitin ligase at the heart of neural development and programmed axon degeneration

  2022cites this paper
• SARM1 can be a potential therapeutic target for spinal cord injury

  2022cites this paper
• Macrophage depletion blocks congenital SARM1-dependent neuropathy

  2022cites this paper
• The macrophage: a key player in the pathophysiology of peripheral neuropathies

  2022cites this paper
• NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

  2022cites this paper
• SARM1 detection in oligodendrocytes but not Schwann cells though sarm1/Sarm1 deletion does not perturb CNS nor PNS myelination in zebrafish and mice

  2022cites this paper
• NMNAT2: An important metabolic enzyme affecting the disease progression.

  2022cites this paper
• Loss-of-function approach using mouse retinal explants showed pivotal roles of Nmnat2 in early and middle stages of retinal development

  2022cites this paper