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Cited by 46Nerve injury and regenerationCell death mechanisms and regulationTraumatic Brain Injury and Neurovascular Disturbances

SARM1 signaling mechanisms in the injured nervous system

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Sambashivan, Shilpa, Freeman, Marc R.·2021·Current Opinion in Neurobiology
DOI 10.1016/j.conb.2021.05.004PMC PMC8387414
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Abstract

Axon degeneration is a prominent feature of the injured nervous system, occurs across neurological diseases, and drives functional loss in neural circuits. We have seen a paradigm shift in the last decade with the realization that injured axons are capable of actively driving their own destruction through the sterile-alpha and TIR motif containing 1 (SARM1) protein. Early studies of Wallerian degeneration highlighted a central role for NAD+ metabolites in axon survival, and this association has grown even stronger in recent years with a deeper understanding of SARM1 biology. Here, we review our current knowledge of SARM1 function in vivo and our evolving understanding of its complex architecture and regulation by injury-dependent changes in the local metabolic environment. The field is converging on a model whereby SARM1 acts as a sensor for metabolic changes that occur after injury and then drives catastrophic NAD+ loss to promote degeneration. However, a number of observations suggest that SARM1 biology is more complicated, and there remains much to learn about how SARM1 governs nervous system responses to injury or disease.

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  • Sarm1 remains inactive in physiological conditions but becomes activated in pathological conditions.

    “For this reason, Sarm1 remains inactive in physiological conditions but becomes activated in pathological conditions 12,48 .”

    From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [48]

    The “Insights into SARM1 activation from structural biology” section (page unavailable) proposes that SARM1 is stabilized in an inactive state under normal physiological conditions and may become activated after injury. The claim presents this proposed mechanism as established and extends injury-related activation to pathological conditions generally. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Sambashivan, S., & Freeman, M. R.
Affiliations
Oregon Health & Science University (US)
Corresponding author
  • Sambashivan, Shilpa
  • Freeman, Marc R.
Venue
Current Opinion in Neurobiology
Publisher
Elsevier BV
Published
2021-08
Volume
69
Pages
247-255
ISSN
0959-4388 (ISSN-L)
DOI
10.1016/j.conb.2021.05.004
PMC
PMC8387414
OpenAlex
W3177063927
Cited by
46
References
2
Citations by year
2026: 5 · 2025: 8 · 2024: 11 · 2023: 15 · 2022: 7
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Neurobiology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Oregon Health and Science University
  • National Institutes of Health (R01 NS059991)
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 › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
SARM1, axonal degeneration, Wallerian degeneration, NAD+ metabolism, axonal injury, axon survival, metabolic sensing, neurodegeneration, axonal signaling
MeSH terms
Animals, Axons, Cytoskeletal Proteins, Wallerian Degeneration, Mice, Knockout, Armadillo Domain Proteins, Mice

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