Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons
Open accessAbstract
The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose 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 which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld(S) neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld(S) does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld(S) protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.
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Three mammalian homologs NMNAT1-3 have been identified, with NMNAT2 being the most labile of the three isoforms with a half-life of approximately 4 h.
“Three mammalian homologs, NMNAT1 -3, have been identified (24)(25)(26), with NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2) being the most labile of the three isoforms with a half-life of ,4 h (27).”
Reducing NMNAT2 levels in cultured mouse superior cervical ganglia neurons induced Wallerian-like degeneration, suggesting NMNAT2 is required to maintain axonal health in the peripheral nervous system.
“Reducing NMNAT2 levels in cultured mouse superior cervical ganglia neurons induced Wallerian-like degeneration, suggesting that NMNAT2 is required to maintain axonal health in the peripheral nervous system (27).”
The neurodegeneration found in Drosophila NMNAT loss-of-function mutants and cultured mouse ganglia neurons with reduced NMNAT2 expression suggests that NMNATs are required to maintain neuronal integrity.
“The neurodegeneration found in Drosophila NMNAT loss-of-function mutants (23) and cultured mouse ganglia neurons with reduced NMNAT2 expression (27) suggests that NMNATs are required to maintain neuronal integrity.”
In neurons, NMNAT2 localizes to Golgi and Rab7-containing late endosomes as well as synaptic terminals and axons.
“In neurons, NMNAT2 localizes to Golgi and Rab7-containing late endosomes as well as to both synaptic terminals and axons (Gilley and Coleman, 2010; Mayer et al., 2010).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Gilley and Coleman, 2010
During axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to critical depletion of NAD+ in the axon.
“during axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to a critical depletion of NAD+ in the axon142,143.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [142]
Wlds mouse studies largely show the neuroprotective function of NMNAT1, NMNAT2 and NMNAT3 and their protective role in several neurodegenerative disorders, including Parkinson disease.
“Overall, Wlds mouse studies largely show the neuro protective function of the biosynthetic enzymes NMNAT1, NMNAT2 and NMNAT3 (REFS142,150–152) and their protective role in several neurodegenerative disorders, including Parkinson disease153–155.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [142]
Under normal physiological conditions, NMNAT2 is a survival factor in axons and must be constantly replenished via anterograde axonal transport due to its rapid turnover.
“During normal physiological conditions, the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) (FIG. 1; BOX 1) is a survival factor in axons, in which it needs to be constantly replenished via anterograde axonal transport due to its rapid turnover142.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [142]
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References 57 · Cited by 472
- Authors
- Gilley, J., & Coleman, M. P.
- Affiliations
- Babraham Institute (GB)
- Corresponding author
- Coleman, Michael P.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-01-26
- Volume
- 8
- Issue
- 1
- Pages
- e1000300
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC2811159
- OpenAlex
- W2033382767
- Cited by
- 472
- References
- 57
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 20 · 2023: 29 · 2022: 50 · 2021: 42 · 2020: 46 · 2019: 32 · 2018: 29 · 2017: 30 · 2016: 22 · 2015: 25 · 2014: 21 · 2013: 29 · 2012: 22
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Medical Research Council (G0300408)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- NMNAT2, axonal degeneration, Wallerian degeneration, axon survival, NMNAT1, NMNAT3, axonal transport, proteasome, therapeutic target
- MeSH terms
- Animals, Axons, Cell Line, Humans, Mice, Inbred C57BL, Nerve Degeneration, Nicotinamide-Nucleotide Adenylyltransferase, Neurites, Rats, Sprague-Dawley, Mice, Rats, Rats, Transgenic
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