DLK, NMNAT2, and SARM1: Judge, Jury, and Executioner in Axon Degeneration

Axon degeneration is a tightly regulated process that plays a central role in the pathogenesis of many neurodegenerative diseases. Three core mediators, DLK (dual leucine zipper kinase), NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), and SARM1 (sterile alpha and TIR motif-containing 1) form a molecular axis that orchestrates axonal self-destruction. Upon stress, DLK initiates mitogen-activated protein kinase signaling, which triggers the expression of prodegenerative genes. NMNAT2, an essential nicotinamide adenine dinucleotide biosynthetic enzyme, is rapidly depleted following injury. Loss of NMNAT2 leads to the accumulation of its substrate, nicotinamide mononucleotide, which in turn activates SARM1, a central executioner of axon degeneration. Together, these proteins constitute a coordinated signaling axis that monitors cellular stress and metabolic cues to regulate axonal integrity. In this review, we provide an overview of the biochemical and cellular mechanisms of DLK, NMNAT2, and SARM1 signaling and discuss how targeting these factors offers opportunities for therapeutic intervention in a broad range of neurodegenerative disorders.