NMNAT2

NMNAT2, or nicotinamide mononucleotide adenylyltransferase 2, is a cytosolic enzyme that participates in NAD+ biosynthesis. It catalyzes the ATP-dependent conversion of nicotinamide mononucleotide (NMN) to NAD+ and pyrophosphate, contributing to cellular NAD+ pools that support energy metabolism and other NAD+-dependent processes. NMNAT2 is one of three NMNAT isozymes in humans, with distinct subcellular localizations and biological roles.

In neurons, NMNAT2 is enriched in axons and dendrites and is transported along microtubules by motor proteins. The enzyme is relatively labile, with a short half-life, and its levels are tightly regulated by proteasomal degradation. This dynamic turnover allows NMNAT2 to respond rapidly to cellular and environmental changes, a feature that is particularly relevant for axon integrity.

A central role of NMNAT2 is in axonal maintenance. It acts as a key defender against SARM1-mediated axon degeneration, a pathway that is activated when NMNAT2 levels fall and NAD+ levels decline. Loss or reduction of NMNAT2 activity can trigger axonal degeneration, while sustained NMNAT2 function helps preserve axons. The Wallerian degeneration slow (WldS) protein, a fusion that includes NMNAT activity, has provided insight into this protective mechanism by slowing degeneration in experimental models.

Clinical and research implications of NMNAT2 include its involvement in neurodegenerative diseases and nerve injury, as well as its potential as a therapeutic target to promote axonal resilience. Ongoing work seeks to clarify its regulatory networks, interaction with SARM1, and prospects for pharmacological modulation.