Axon fibres are uniquely vulnerable to injury, and the conserved program of injury-induced axon degeneration, termed Wallerian degeneration, is analogous to the early events characterising neuropathies such as Parkinson’s and Alzheimer’s disease (1, 2). Understanding the molecular mechanisms of Wallerian degeneration is therefore vital for treating these debilitating diseases. The most well-studied protein in the Wallerian degeneration pathway is SARM1, a TLR-adaptor protein with NADase activity regulated by changes in NAD metabolism post axonal injury. SARM1 autoinhibition in humans is thought to be mediated by disruption of the cellular ratio of NAD+ and its precursor, NMN, with competitive binding of these metabolites to the inhibitory ARM domain of the SARM1 protein leading to conformational changes and release of inhibition (3). To validate this hypothesis, the ARM domain of Drosophila SARM1 was co-crystallised with NAD+ for structural comparison with the previously solved dSARM1ARM conformational states. Unexpectedly, dSARM1ARM was shown to bind NAD+ similarly to NMN, in the proposed active conformation. Nanobodies were utilised to further investigate the effects of ligands on dSARM1 conformation and activation, which surprisingly revealed dSARM1 was not activated by NMN. Together, the structural and functional characterisation of dSARM1ARM indicates the mechanism of dSARM1 regulation may differ from that of human SARM1.