Cited by 594Nerve injury and regenerationCell death mechanisms and regulationPain Mechanisms and Treatments

SARM1 activation triggers axon degeneration locally via NAD + destruction

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Gerdts, Josiah, Brace, E.J., Sasaki, Yo, DiAntonio, Aaron, Milbrandt, Jeffrey·2015·Science

Abstract

SARM1-driven axon degeneration: Axons, the long protrusions of nerve cells, are programmed to self-destruct under certain conditions that occur during development, stress, or disease states. Gerdts et al. outline a biochemical mechanism that controls such axon degeneration. The authors designed versions of SARM1 (sterile alpha and TIR motif—constraining 1) that could be activated or inhibited in cells. Their experiments showed that the activation of SARM1 was necessary and sufficient to cause axon destruction in cultured mouse neurons. SARM1-mediated destruction was associated with depletion of the metabolic cofactor NAD + from cells. Science , this issue p. 453

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  • Sarm1 TIR domain cleaves NAD+ into cyclic ADP-ribose (cADPR) as a new class of NAD+ hydrolases.

    “Subsequent work showed that Sarm1 TIR domain cleaves NAD + into cyclic ADP-ribose (cADPR) as a new class of NAD + hydrolases 10,44”

    From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [10]

    The passage on NAD+ consumption (section labeled Abstract; no page available) reports that SARM1 TIR dimerization causes NAD+ consumption and nicotinamide release. It does not identify cyclic ADP-ribose as a product or establish that the TIR domain itself is a new class of NAD+ hydrolases. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • SARM1-mediated NAD+ degradation plays a key role in axonal degeneration after axonal injury.

    “However, SARM1-mediated NAD+ degradation plays a key role in axonal degeneration after axonal injury60 (see the section Neurodegeneration).”
  • SARM1 plays an undisputed key role in axonal degeneration and is emerging as a therapeutic target to prevent or ameliorate neurodegenerative diseases and traumatic brain injuries.

    “Despite its controversial role in immune cells, SARM1 plays an undisputed key role in axonal degeneration and is emerging as a therapeutic target to prevent or ameliorate neurodegenerative diseases and traumatic brain injuries (as discussed in the section Neurodegeneration).”
  • SARM1 is activated by axonal injury and mediates axonal degeneration by promoting NAD+ degradation.

    “the NAD+-consuming enzyme SARM1 is activated by axonal injury and mediates axonal degeneration by promoting NAD+ degradation60.”
  • Sarm1-knockout mice are protected from axonal degeneration and can rescue severe axon growth defects and perinatal death induced by lack of NMNAT2.

    “Sarm1-knockout mice are protected from axonal degeneration60 and can rescue the severe axon growth defects and perinatal death induced by lack of NMNAT2 (REFS147,148).”

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Authors
Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A., & Milbrandt, J.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Milbrandt, Jeffrey
Venue
Science
Published
2015-04-24
Volume
348
Issue
6233
Pages
453-457
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2062200458
Cited by
593
References
27
Citations by year
2026: 42 · 2025: 63 · 2024: 50 · 2023: 73 · 2022: 82 · 2021: 71 · 2020: 70 · 2019: 43 · 2018: 35 · 2017: 26 · 2016: 28 · 2015: 10
FWCI
15.32
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (RO1DA020812, RO1AG013730, RO1NS065053, RO1NS087632, RO1NS078007, F31NS074517)
  • Vertex Pharmaceuticals
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords
SARM1, axonal degeneration, NAD+ depletion, axonal injury, axon protection, NAD+ synthesis, neurodegeneration
MeSH terms
Animals, Axons, Cytoskeletal Proteins, Humans, NAD, Neurons, Wallerian Degeneration, Mice, Knockout, Armadillo Domain Proteins, Mice, Protein Multimerization, HEK293 Cells, Peripheral Nerve Injuries

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