2. Academic Validation
  3. SARM1 is an essential component of neuronal Parthanatos

SARM1 is an essential component of neuronal Parthanatos

  • bioRxiv. 2025 May 15:2025.05.14.654090. doi: 10.1101/2025.05.14.654090.
Tong Wu 1 2,  Liya Yuan 1,  Yo Sasaki 1,  William Buchser 1 3,  A Joseph Bloom 1 4,  Aaron DiAntonio 4 5,  Jeffrey Milbrandt 1 4 6
Affiliations

Affiliations

  • 1 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA 63110.
  • 2 Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA 63130.
  • 3 Functional Imaging for Variant Elucidation at the McDonnell Genome Institute, St. Louis, MO, USA 63110.
  • 4 Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, USA 63110.
  • 5 Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA 63110.
  • 6 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA 63110.
PMID: 40463025 DOI: 10.1101/2025.05.14.654090
Abstract

The NAD+ hydrolase SARM1 is the central executioner of pathological axon degeneration. SARM1 is allosterically activated by an increased NMN/NAD+ ratio resulting from depletion of NAD+ or accumulation of its precursor, NMN, typically due to loss of the labile NAD+ synthetase NMNAT2 following axon injury. Another NAD+ hydrolase, PARP1, is hyperactivated by DNA damage, triggering the Parthanatos cell death pathway. We demonstrate that multiple mechanistically-distinct DNA-damaging agents lead to SARM1 activation and axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of PARP1 activation by DNA damage that are pathognomonic of Parthanatos, including mitochondrial depolarization, nuclear translocation of AIF (apoptosis-inducing factor), and cell death. Moreover, SARM1 mediates glutamate excitotoxicity, a clinically significant pathomechanism attributed to Parthanatos. The identification of SARM1 as an essential component of neuronal Parthanatos, a major contributor to cell death in neurodegenerative disease, greatly expands the potential clinical utility of SARM1 inhibitors.

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