DNA damage triggers neuron self-destruction

Over the past decade, researchers at WashU Medicine have consistently demonstrated that the SARM1 molecule is a central trigger for the destruction of axons. The loss of these structures is a common feature of numerous neurological conditions, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, glaucoma, and peripheral neuropathies, including those caused by chemotherapy.

Now, a team of scientists led by Jeffrey Milbrandt and Aaron DiAntonio has shown that it is DNA damage that can activate SARM1, triggering a cascade of events that ends with the death of nerve cells. However, the causes of DNA damage can be different. For example, these include oxidative stress due to neuroinflammation, mitochondrial dysfunction, as well as the effects of certain chemotherapeutic drugs that intentionally damage the DNA of cancer cells, but at the same time injure nerves, causing neurotoxicity.

The key link was a pathway known as parthenogenesis, a form of programmed cell death associated with Parkinson’s disease. It is triggered by the overactivation of the PARP1 enzyme, which is normally involved in repairing damaged DNA. When PARP1 becomes overactive, it leads to the depletion of cellular energy resources and triggers destructive processes.

In the new study, the researchers demonstrated in mouse and human cells that DNA damage activates SARM1 through this pathway. Thus, a direct link has been established between genetic damage, PARP1 activation, SARM1 inclusion, and subsequent axon degradation and neuronal death.

Since SARM1 is a common method of axon destruction, regardless of the underlying cause of damage, its inhibition could be a universal strategy for protecting neural tissue. SARM1 inhibitors have the potential to preserve the integrity of axons even in the face of various diseases and injuries, making them promising candidates for the treatment and prevention of neurodegeneration.

This idea has already made its way from the lab to the clinic. Milbrandt and DiAntonio founded the biotechnology startup Disarm Therapeutics, which was acquired by Eli Lilly in 2020. Currently, SARM1 inhibitors are undergoing clinical trials, and researchers are evaluating their safety and effectiveness in patients.