2. Academic Validation
  3. SARM1 executes neuronal parthanatos and promotes excitotoxic cell death

SARM1 executes neuronal parthanatos and promotes excitotoxic cell death

  • Neuron. 2026 Apr 16:S0896-6273(26)00218-7. doi: 10.1016/j.neuron.2026.03.027.
Tong Wu 1,  Liya Yuan 2,  Yo Sasaki 2,  Si Jia Chen 3,  William Buchser 4,  A Joseph Bloom 5,  Aaron DiAntonio 6,  Jeffrey Milbrandt 7
Affiliations

Affiliations

  • 1 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
  • 2 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Functional Imaging for Variant Elucidation at the McDonnell Genome Institute, St. Louis, MO 63110, USA.
  • 5 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO 63110, USA.
  • 6 Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].
  • 7 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].
PMID: 41997149 DOI: 10.1016/j.neuron.2026.03.027
Abstract

The nicotinamide adenine dinucleotide (NAD+) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD+ ratio. DNA damage induces NAD+ loss and an increased NMN/NAD+ ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP+) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.

Keywords

ALS; NAD⁺ metabolism; Parkinson’s disease; SARM1; dopaminergic neurons; excitotoxicity; iPSC; neurodegeneration; parthanatos; stroke.

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