SARM1 is the key executioner enzyme for axon degeneration. In a healthy neuron, SARM1 exists in an enzymatically “off” state. Axon injury turns on SARM1’s activity to hydrolyze the important metabolite NAD+, leading to metabolic crisis and axon fragmentation. The mechanism underlying SARM1 activation by axon injury was discovered in a recent study from the lab published in Neuron. It was previously known that loss of the axon survival factor NMNAT2 leads to SARM1 activation, but it was unknown how this occurs.
SARM1 is the key executioner enzyme for axon degeneration. In a healthy neuron, SARM1 exists in an enzymatically “off” state. Axon injury turns on SARM1’s activity to hydrolyze the important metabolite NAD+, leading to metabolic crisis and axon fragmentation. The mechanism underlying SARM1 activation by axon injury was discovered in a recent study from the lab published in Neuron. It was previously known that loss of the axon survival factor NMNAT2 leads to SARM1 activation, but it was unknown how this occurs.
This research was a collaboration between the DiAntonio/Milbrandt labs and two Australian research teams, Thomas Ve’s group at Griffith University and Bostjan Kobe’s group at the University of Queensland. Using an array of structural, biochemical, biophysical and cellular assays, Figley et al. found that SARM1 activation is tuned to the ratio of two key metabolites in the axon, NMN and NAD+. The axon survival factor NMNAT2 usually converts NMN into NAD+, but when its levels are decreased in injury or disease, NMNAT2’s substrate NMN accumulates and its product NAD+ decreases.
Figley et al. found that SARM1’s ARM domain is able to directly bind to either NMN or NAD+. In a healthy neuron, NAD+ binding is associated with the “off” state for SARM1, but NMN binding results in a conformational change of the ARM domain that allows for multimerization of SARM1’s TIR domains and activation of its destructive NADase activity. Thus, when NMNAT2 is degraded after axon injury or in disease, the NMN/NAD+ ratio increases, and SARM1 is activated, resulting in axon degeneration. The discovery of an allosteric region in SARM1 opens exciting possibilities for the design of novel drug inhibitors or activators of SARM1.