2026-07-01 ワシントン大学セントルイス校
＜関連情報＞
- https://source.washu.edu/2026/07/dna-damage-can-trigger-neurons-to-self-destruct/
- https://www.cell.com/neuron/fulltext/S0896-6273(26)00218-7
SARM1は神経細胞のパルタナトスを実行し、興奮毒性細胞死を促進する SARM1 executes neuronal parthanatos and promotes excitotoxic cell death
Tong Wu ∙ Liya Yuan ∙ Yo Sasaki ∙ … ∙ A. Joseph Bloom ∙ Aaron DiAntonio ∙ Jeffrey Milbrandt
Neuron Published:April 16, 2026
DOI:https://doi.org/10.1016/j.neuron.2026.03.027
Highlights
- DNA damage activates SARM1 to drive mitochondrial depolarization and axon loss
- PARP1 hyperactivation engages SARM1 to execute neuronal parthanatos
- SARM1 inhibition blocks AIF translocation and neuronal death in parthanatos
- SARM1 inhibition protects neurons in FUS-ALS, Parkinson’s disease, and excitotoxicity models
Summary
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.
