Low NMNAT2 Triggers SARM1 Activity and Alters Nicotinamide Riboside Response in Axons: Preclinical Findings

Synopsis

NMNAT2 is a key protein that keeps axons healthy by blocking the pro-degenerative protein SARM1. Completely losing NMNAT2 in mice causes severe axon loss and early death, but removing SARM1 prevents these effects. Mice with partially reduced NMNAT2 appear normal at birth and into old age but develop subtle axon defects and behavioral changes. Chronically low NMNAT2 levels reduce prenatal survival in a SARM1-dependent way and cause mild SARM1 activation in otherwise normal axons, leading to lower NAD(P) levels and reduced neurite growth. Low NMNAT2 also blocks the NAD-boosting effects of nicotinamide riboside in axons. Overall, reduced NMNAT2 can trigger low-level SARM1 activity, which may predispose to axonal disorders.

Journal

Molecular Neurobiology