An NAD+/NMN balancing act by SARM1 and NMNAT2 controls axonal degeneration

Abstract

Axonal degeneration is controlled by the TIR domain NADase SARM1. In this issue of Neuron, Figley et al. (2021) reveal a key regulatory mechanism that controls SARM1's enzymatic activity, providing insight into how NAD+ biosynthesis by the NMNAT2 enzyme protects axons, and a new therapeutic path to tune SARM1 activity.

Figure 1.. NAD+ and its precursor NMN compete for the same binding site to switch SARM1 between locked and activated states

NAD+ binding to a regulatory site in SARM1’s ARM domain stabilizes an ARM-TIR interaction that locks the TIR domains in an inactive state. The NAD+ precursor NMN binds to this same site but switches the ARM conformation to disrupt the ARM-TIR lock, freeing the TIR domains to associate into an activated NADase enzyme. In healthy axons, the presence of NMNAT2 maintains NAD+ levels while consuming NMN as a reactant, favoring the NAD+-bound locked state. In contrast, in distal axons disconnected from the cell body by injury and/or disrupted axonal transport, reduced NAD+ biosynthesis favors NMN binding to unlock the NADase enzyme. NAD+ breakdown in the absence of NMNAT to reduce the NMN/NAD+ ratio leads to unmitigated NADase activity by activated SARM1, which leads to metabolic catastrophe and axonal degeneration. The SARM1 cartoon is adapted from Sporny et al. (2020).