NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion
Open accessAbstract
Overexpression of the NAD+ biosynthetic enzyme NMNAT1 leads to preservation of injured axons. While increased NAD+ or decreased NMN levels are thought to be critical to this process, the mechanism(s) of this axon protection remain obscure. Using steady-state and flux analysis of NAD+ metabolites in healthy and injured mouse dorsal root ganglion axons, we find that rather than altering NAD+ synthesis, NMNAT1 instead blocks the injury-induced, SARM1-dependent NAD+ consumption that is central to axon degeneration.
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Wlds mice are protected from axonal degeneration, show absence of SARM1 expression and higher neuronal NAD+ levels due to overexpression of a chimeric NMNAT1 fusion protein that redistributes to the axon and substitutes for NMNAT2.
“Wallerian degeneration slow (Wlds) mice, which are protected from axonal degeneration, showing absence of SARM1 expression144 and higher neuronal NAD+ levels, owing to the overexpression of a chimeric fusion protein of NMNAT1, which allows its redistribution from the nucleus to the axon, where it can substitute for the activity of NMNAT2 (REFS145,146).”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [146]
Restoration of NAD+ levels with NAD+ supplements and overexpression of NAMPT and NMNAT1 prevents axon degeneration.
“Restoration of NAD+ levels with NAD+ supplements and the overexpression of the two biosynthetic enzymes NAMPT and NMNAT1 were found to prevent axon degeneration60,146.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [146]
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References 25 · Cited by 192
- Authors
- Sasaki, Y., Nakagawa, T., Mao, X., DiAntonio, A., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- University of Toyama (JP)
- Corresponding author
- Sasaki, Yo
- DiAntonio, Aaron
- Milbrandt, Jeffrey
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-10-13
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5063586
- OpenAlex
- W2531683815
- Cited by
- 192
- References
- 25
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 11 · 2023: 18 · 2022: 22 · 2021: 29 · 2020: 25 · 2019: 24 · 2018: 21 · 2017: 20
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (KAKENHI 24609019)
- National Institutes of Health (RO1NS065053, RO1NS087632, RO1AG013730)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- NMNAT1, SARM1, axonal degeneration, NAD+ depletion, NAD+ metabolism, dorsal root ganglia, axonal injury, NAD biosynthesis, axon protection, nicotinamide mononucleotide
- MeSH terms
- Animals, Axons, Cytoskeletal Proteins, Ganglia, Spinal, NAD, Nerve Degeneration, Nicotinamide-Nucleotide Adenylyltransferase, Armadillo Domain Proteins, Mice
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