Two new studies from the Washington University School of Medicine in St. Louis support the idea of making a therapy for neurodegenerative diseases that works for a wide range of patients and targets a chemical that is the main cause of axon loss, which is when the wiring of the nervous system breaks down.
By blocking this molecular killer, axon loss, which has been linked to many neurological diseases like Parkinson’s, glaucoma, and amyotrophic lateral sclerosis (ALS), can be stopped.
The two recent findings, which were both released on October 26 in the Journal of Clinical Investigation, shed unexpected light on the mechanism by which the chemical known as SARM1 causes axon death, which is at the root of the emergence of neurodegenerative illnesses. The study also suggests novel therapeutic strategies for conditions characterized by axon loss.
According to co-senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics, “We urgently need medicines for neurodegenerative illnesses.” “We are particularly interested in learning how to block SARM1 via small molecule inhibitors or gene therapy methods given the evidence of its crucial role in these disorders. Our most recent research indicates that we might also be able to prevent it from causing harmful neuroinflammation. We are optimistic that our research will result in efficient new treatments for a variety of neurodegenerative and neuroinflammatory illnesses.
As Milbrandt and co-senior author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, discovered in 2017, SARM1 is an enzyme that can contribute to neurodegeneration.The discovery of pharmacological molecules that inhibit SARM1 for the treatment of disorders characterized by axon degeneration was subsequently accelerated by the co-founding of a startup firm named Disarm Therapeutics. Eli Lilly and Company bought Disarm Therapeutics in 2020 to speed up the development of treatments for neurological disorders that target SARM1.
SARM1 is never turned on in healthy neurons. But SARM1 turns on when there is an injury or an illness. SARM1 is an arsonist when it is activated because it consumes so much cellular energy that the axons can’t survive. Axons begin to dissolve as a result of the energy crisis.
The researchers looked into a mystery and incredibly rare progressive neuropathy illness that is so uncommon that it has no name in order to learn more about the function of SARM1 in causing axon damage. This uncommon situation ended up serving as a useful metaphor for comprehending the immune system’s function in neuroinflammatory disorders more broadly. By sequencing the patient genomes, the axon loss was discovered to be caused by genetic flaws in the gene NMNAT2, whose normal function maintains SARM1 off. These genetic mistakes result in persistent SARM1 activation, which results in axon degeneration. The researchers then replicated these alterations in mice using the CRISPR gene-editing method. These mice developed into adulthood just like people with the syndrome, but they experienced increased motor impairment, a loss of peripheral axons, and, most significantly, an invasion of immune cells known as macrophages.
The discovery that fewer macrophages in the body prevented axon loss and illness symptoms in mice astonished the researchers. According to the study, SARM1 not only directly contributes to axon loss but also plays a role in causing neuroinflammation, which only makes matters worse. The results also suggest that immunosuppressants that stop macrophages or other immune cells that cause inflammation could be used to treat neurodegenerative diseases.
A frequent type of inherited peripheral neuropathy and a useful model for studying axon loss in general, Charcot-Marie-Tooth disease type 2a, was the subject of the second paper’s investigation into the potential role of SARM1. Patients who have this condition gradually lose their motor and sensory axons, which results in muscle weakness, trouble walking, and tingling or burning in their hands and feet. The disease is brought on by a mutation in a crucial protein found in mitochondria, the cell’s energy production centers. The mitofusin2 protein mutation affects how normally the mitochondria operate. Many studies have focused on the abnormal mitochondria because it is thought that they are the main cause of the disease.
Surprisingly, the scientists discovered that eliminating SARM1 in a rat model of Charcot-Marie-Tooth syndrome type 2a prevented the majority of the issues the animals displayed—independent of the afflicted mitochondria. Eliminating SARM1 prevented or reduced axon degeneration, muscle atrophy, anomalies in the mitochondria, and issues with neuromuscular junctions, which are the points at which neurons and muscle converge. Even though the mutant mitofusin2 protein was still there, deleting SARM1 stopped the mitochondria from getting worse and becoming less useful.
In addition to protecting the axons, blocking SARM1 results in significantly healthier mitochondria, according to DiAntonio. This was a complete surprise, but mitochondrial dysfunction is a common part of many neurodegenerative diseases, like Parkinson’s, so we are hopeful that it may be useful.
