NAD and axon degeneration: From the Wlds gene to neurochemistry

Neurodegenerative diseases have become a global issue due to the aging population. These disorders affect a vast patient population and represent a huge area of unmet therapeutic need. Axon degeneration is a common pathological character of those neurodegenerative diseases. It results in the loss of communication between neurons. Two decades ago, the Wallerian degeneration slow (Wlds) mouse strain was identified, in which the degeneration of transected axons is delayed. The phenotype is attributed to the over-expression of a chimeric protein Wlds which contains a short fragment of the ubiquitin assembly protein UFD2 and the full-length nicotinamide adenine dinucleotide (NAD) synthetic enzyme Nicotinamide mononucleotide adenylyl-transferase-1 (Nmnat-1). However, the underlying molecular mechanism remains largely unknown. Recently, it’s reported by independent researchers that the full length coding sequence of mouse Nmnat-1 could mimic the axonal protective effect of the Wlds gene when over-expressed in primary neural cultures. Together with a significant number of subsequential reports, this finding highlighted the substantial role of nicotinamide adenine dinucleotide (NAD) in the process of axon degeneration. Here we reviewed the history of axon degeneration research from a neurochemical standpoint and discuss the potential involvement of NAD synthesis, NAD consumption, and NAD-dependent proteins and small molecules in axon degeneration.