Wallerian degeneration: an emerging axon death pathway linking injury and disease

Recent work has identified novel modifiers of axon degeneration following injury, known as Wallerian degeneration, and new examples of convergence between this mechanism and axon degeneration occurring in some neurodegenerative diseases. Coleman and colleagues outline our current understanding of the Wallerian degeneration pathway and consider its links to disease mechanisms. Axon degeneration is a prominent early feature of most neurodegenerative disorders and can also be induced directly by nerve injury in a process known as Wallerian degeneration. The discovery of genetic mutations that delay Wallerian degeneration has provided insight into mechanisms underlying axon degeneration in disease. Rapid Wallerian degeneration requires the pro-degenerative molecules SARM1 and PHR1. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is essential for axon growth and survival. Its loss from injured axons may activate Wallerian degeneration, whereas NMNAT overexpression rescues axons from degeneration. Here, we discuss the roles of these and other proposed regulators of Wallerian degeneration, new opportunities for understanding disease mechanisms and intriguing links between Wallerian degeneration, innate immunity, synaptic growth and cell death.