Axonal degeneration is a subcellular self-destruction program. It occurs during normal aging, but also contributes to axon pathology and represents a common and prominent feature of a range of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, in their early phases. SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) is a central executioner in injury-induced axon degeneration. The loss of SARM1 provides axonal protection after injury and in several neurodegenerative disease conditions. SARM1 exists as ring-shaped octamers, mediated by two central tandem SAM (sterile alpha-motif) domains. In healthy axons, SARM1 is held in an inactive state by the N-terminal ARM (armadillo repeat motif) domain. Upon injury, this auto-inhibition is relieved, permitting the C-terminal TIR (Toll/interleukin-1 receptor) domains to begin cleaving NAD+ into nicotinamide, and either ADPR (ADP-ribose) or cADPR (cyclic ADP-ribose). These changes in turn trigger an intracellular Ca2+ influx, a corresponding ATP loss and eventually axon degeneration. Despite its vital role in this process, the mechanism of SARM1 activation remains obscure.
Here, we show that the NAD+ precursor NMN (nicotinamide mononucleotide), interacts directly with the N-terminal ARM domain. We determined the crystal structure of the NMN-bound ARM domain from Drosophila SARM1 ortholog, revealing an unusual closed conformation of the right-handed superhelix, with both termini collapsed onto NMN. Together with mutagenesis, we identified the residues important for NMN interaction and demonstrated that this interaction is important for initiating SARM1 activation. The result sheds light on the mechanism of the NMN-induced SARM1 activation, enhances our understanding of SARM1-induced axon degeneration and enables a path to the development of allosteric SARM1 inhibitors that block SARM1 activation.