Molecular Studies of SARM1, an Axonal Self-Destruction Switch

Axons are neuronal extensions that make up the wiring of the nervous system. Recent studies have revealed that axons possess a unique and largely uncharacterized self-destruction program that may be a therapeutic target for diseases in which axon loss contributes to disability. We have developed a scalable assay of axon degeneration that allows quantitative screening for agents that alter axon degeneration. From a library of bioactive compounds, we have identified and characterized several novel axon-protective compounds. Using this system we screened a genome-scale lentiviral shRNA library to identify proteins that promote axon degeneration following injury. A top hit in this screen was the protein SARM1, and validation experiments and the work of others confirm that SARM1 is a central regulator of axon destruction. Combining structure-function and biochemical studies, we have developed a working model of SARM1-mediated axon destruction: SARM1 complexes are present within axons and are held inactive by an auto-inhibitory N-terminus. Following injury, SARM1 activation leads to dimerization of the SARM1 Toll-Interleukin Receptor (TIR) domain, which is sufficient to trigger a program of rapid NAD+ breakdown leading to axon destruction