SARM1 Drives Nerve Damage Following Inflammation and Cell Death Signals: Preclinical Findings

Synopsis

Neuroinflammation and a type of cell death called necroptosis play big roles in neurodegenerative diseases, often starting with damage to nerve fibers called axons. SARM1 is a key enzyme that causes axons to break down. This study shows how inflammation and necroptosis work together to trigger axon loss. In a neuroinflammatory model of glaucoma, the inflammatory molecule TNF-α causes SARM1 to activate, leading to axon damage, loss of support cells (oligodendrocytes), and death of nerve cells in the eye. TNF-α also causes axon damage in sensory nerves through a special necroptosis process. Normally, a protein called MLKL carries out necroptosis, but in axons, MLKL doesn't cause damage directly. Instead, MLKL causes important axon survival proteins (NMNAT2 and STMN2) to disappear. Without these proteins, SARM1 becomes active and breaks down NAD+, which lets calcium into the axon and causes it to die. This work identifies a unique way axons die during neuroinflammation and shows that blocking SARM1 might help stop nerve damage in diseases like glaucoma.

Journal

Journal of Cell Biology