Axonal death 2: Axon Degeneration: Molecular Mechanisms and Therapeutic Potential
Axon degeneration is an early event contributing to morbidity and progression of neurodegenerative diseases including peripheral neuropathy, multiple sclerosis, ALS, and Parkinson’s disease. Axon degeneration is active program of subcellular destruction, akin to apoptosis but using a distinct molecular program. We have defined a central molecular mechanism driving axon loss in the injured and diseased nervous system, dissecting the central role of the pro-degenerative molecule SARM1. We discovered that SARM1 is the founding member of an evolutionarily conserved family of NAD+ cleaving enzymes and that SARM1 promotes axon degeneration via local disruption of neurometabolism in the axon. The identification of SARM1 as an enzyme is enabling the development of small molecule and gene therapy methods for blocking SARM1 function. We will discuss recent mechanistic insights into the SARM1 axon degeneration pathway and how these new molecular insights may enable the development of novel therapeutics for the prevention and treatment of neurological diseases characterized by axon loss.