The loss of axons (nervous system wiring) has been responsible for various neurodegenerative diseases such as peripheral neuropathies, Parkinson’s disease, glaucoma, and amyotrophic lateral sclerosis (ALS).
According to a recent article in Newswise, researchers at Washington University’s School of Medicine are developing a treatment that will target a molecule that is responsible for the death of axons. The molecule is called SARM1.
The Journal of Clinical Investigation published two new studies appearing in its October 26th issue. The first study details the way in which SARM1 causes the death of axons and neurodegenerative diseases. Researchers described new therapeutic programs for disorders caused by the loss of axons.
The Need for Treatment
Dr. Jeffrey Milbrandt, the study’s co-senior author, said that they have proof of SARM1’s influence on these diseases. Therefore, the teams are especially interested in blocking SARM1’s ability to cause neuroinflammation.
In 2017 Dr. Milbrandt and his co-senior author Dr. Aaron DiAntonio found that SARM1 promotes neurodegeneration. The doctors co-founded a company they named Disarm Therapeutics that develops compounds inhibiting SARM1 to treat disorders defined as axon degeneration. Eli Lilly acquired Disarm Therapeutics in 2020 to advance SARM1 therapies.
SARM1 is normally switched off. However, an injury or a disease will activate it. Once active, it burns cellular energy to a point that causes axons to disintegrate.
The researchers found an unnamed rare disease that acted as a model to help them understand the immune system’s role in neuroinflammatory disorders. They discovered generic errors in a gene called NMNAT2 which normally keeps SARM1 switched off. But because of these errors SARM1 remained activated causing axon destruction.
CRISPR to the Rescue
CRISPR’s gene editing platform was used to reproduce the mutation in the mouse models. Similar to humans, the mice lived into adulthood but with increasingly deteriorating motor dysfunction and loss of axons. Most importantly, immune cells (macrophages) invaded their system.
The researchers discovered that a reduction in macrophages not only stopped but reversed axon loss in mice as well as lessened symptoms of the disease. They note that SARM1 is a direct cause of axon loss and is responsible for exacerbating neuroinflammation.
The Second Study
The second paper discussed the potential of SARM1 for type 2a Charcot-Marie-Tooth (CMT) disease. It is thought to be a satisfactory model for studying axon loss.
CMT causes loss of sensory and motor axons. Patients develop muscle weakness that results in difficulty walking. A mitofusin2 protein mutation disrupts the mitochondria which are responsible for the production of a major portion of a cell’s energy.
Deleting SARM1
When the researchers deleted SARM1 from a CMT type 2a mouse model, they were surprised to learn that a major portion of symptoms had been resolved. By eliminating SARM1, the axons were protected, and the mitochondria were stabilized.
Dr. DiAntonio said that they are hopeful their findings may be relevant to Parkinson’s and other disorders where mitochondrial dysfunction exists.
