SARM1 Ring to Rule Them All

SARM1 is a central executor of neurodegeneration. Remarkably, neurons from SARM1 knock-out mice (which appear to be normal in many respects) show prolonged resistance for neuronal degeneration after mechanical damage, oxidative stress, and chemotherapy treatments. Mechanistically, SARM1 contains NADase activity, which, in response to nerve injury, depletes the key cellular metabolite, NAD+. To gain structural knowledge of SARM1 we use X-ray crystallography of isolated SARM1 domains and single particle EM 3D reconstruction of the intact protein. We discovered that SARM1, like other apoptotic complexes, assembles into an oligomeric ring. Structure analysis and additional experiments in cultured cells points at a surprising molecular mechanism by which SARM1 is kept inactive during homeostasis and how it becomes activated in response to metabolic and oxidative stress conditions