Changes in NMN/NAD+ Ratio Activates SARM1 to Trigger Nerve Damage: Preclinical Findings

Synopsis

Axon degeneration is a key feature of many neurodegenerative diseases. SARM1 is an enzyme that breaks down NAD+ and, when activated, causes axon destruction. The enzyme NMNAT2 normally converts NMN to NAD+, but when NMNAT2 is lost, SARM1 is activated by an increased ratio of NMN to NAD+. Both NMN and NAD+ bind to the same part of SARM1, competing with each other. Structural studies show how NMN binding changes SARM1's shape, and mutating the binding site stops SARM1 activation and axon damage after injury. Thus, SARM1 acts as a metabolic sensor detecting high NMN/NAD+ ratios, triggering NAD+ breakdown and leading to axon degeneration.

Journal

Neuron