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, PhD, the James S. McDonnell Professor of Genetics and executive director of the McDonnell Genome Institute, and Aaron DiAntonio, MD, PhD, 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 start-up company 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 gets switched on had been elusive.
In the new study — co-led by first author Tong Wu, PhD, a postdoctoral researcher in Milbrandt’s lab — the authors show 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.
A key feature of pathanatos is extreme overactivation of PARP1, which is part of a DNA repair pathway that is often turned on in states of disease or injury. PARP1 consumes large amounts of a key cellular fuel molecule called NAD as it attempts to repair damaged DNA. The researchers showed when these fuel levels drop SARM1 is activated.
Also a fuel hog, SARM1 burns through the rest of the cell’s energy supply, triggering the destruction of axons and cell death. Eliminating or blocking SARM1 reduced these destructive effects, according to the study.
By linking DNA damage signaling to SARM1 activation, this study brings together two previously separate explanations for how nerve cells die — one involving DNA damage and the other axon self-destruction — and highlights SARM1 as a convergence point where different disease-relevant stresses can funnel into the same destructive endpoint. This expands the relevance of SARM1 to more neurodegenerative diseases than previously thought, including disorders with distinct and unrelated causes but that converge on DNA damage and loss of cellular fuel, including Parkinson’s disease, ALS and acute brain injuries, among others.