DNA damage can trigger neurons to self-destruct

by Washington University in St. Louis

edited by Lisa Lock, reviewed by Robert Egan

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Over the past decade, researchers at WashU Medicine have established that a molecule called SARM1 is a central trigger in the loss of axons, the vital wiring of the nervous system. Axon loss is characteristic of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, glaucoma and peripheral neuropathies, including those caused by common chemotherapies.

Now, in a new study published in Neuron, the researchers showed how DNA damage triggers SARM1, leading to axon loss and nerve cell death. DNA damage has many causes, including oxidative stress from neuroinflammation and mitochondrial dysfunction, both of which can initiate neurodegenerative diseases. Importantly, common chemotherapies that intentionally damage DNA to kill cancer cells also injure nerves and contribute to chemotherapy-related neurotoxicity.

Interventions that inhibit SARM1—helping keep axons intact regardless of the disease or injury—show promise for treatment and prevention, according to research led by Jeffrey Milbrandt, MD, Ph.D., the James S. McDonnell Professor of Genetics and executive director of the McDonnell Genome Institute, and Aaron DiAntonio, MD, Ph.D., the Alan A. and Edith L. Wolff Professor of Developmental Biology, both at WashU Medicine. To help bring such therapies to patients, Milbrandt and DiAntonio co-founded a WashU biotech startup called Disarm Therapeutics, which was acquired by Eli Lilly in 2020. SARM1 inhibitors are now being evaluated in clinical trials.

Even so, the precise way the SARM1 molecule is switched on had been elusive.

In the new study—co-led by first author Tong Wu, Ph.D., a postdoctoral researcher in Milbrandt's lab—the authors showed in mouse and human cells that DNA damage can trigger SARM1's destructive mechanism through a well-known cell death pathway called parthanatos, a form of cell death associated with Parkinson's disease that is driven by overactivation of a DNA repair enzyme called PARP1.

Publication details

Tong Wu et al, SARM1 executes neuronal parthanatos and promotes excitotoxic cell death, Neuron (2026). DOI: 10.1016/j.neuron.2026.03.027

Journal information: Neuron

Key medical concepts

SARM1 protein, humanDNA Damage

Clinical categories

Neurology Provided by Washington University in St. Louis Who's behind this story?

Lisa Lock

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Robert Egan

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