The SARM1 Axon Degeneration Pathway: Mechanistic Insights and Therapeutic Opportunities

Abstract

Axon loss drives morbidity and progression of many common neurological diseases including peripheral neuropathy, glaucoma, traumatic brain injury, multiple sclerosis, and neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, and ALS. Axon degeneration is a genetically encoded program of subcellular self-destruction. We use Drosophila, mice, and human iPSC-derived neurons to define the molecular mechanisms of the axon degeneration pathway. We identified SARM1 as the central executioner of the axonal degeneration program and demonstrated that it is the founding member of an ancient class of enzymes that cleave the essential metabolite NAD. Using these mechanistic insights, we have developed small molecule inhibitors to block the SARM1 pathway that are currently in clinical trials as potential therapies for neurodegenerative disease.