Delayed Wallerian degeneration of sympathetic axons: A potential role of NAD+ and the MEK/Erk pathway

Axon death is an important feature in development of both the nervous system and in a variety of neuron degenerative diseases. Until recently, death of an axon was thought to occur passively, but this view changed with the discovery of a naturally occurring mutation in mice called Wallerian degeneration slow (Wlds) (Lunn et al., 1989). Wlds-mediated delays in degeneration were associated with the expression of a fusion protein that expressed an incomplete E4 ligase and a functional nicotinamide mononucleotide adenylytransferase-1 (Nmnat-1). Delays in axonal degeneration were originally thought to be caused by the incomplete E4 ligase, but recent studies have shifted focus onto the role of Nmnat-1. Nmnat-1 is responsible for the formation of NAD, and this body of work focused on the effects of exogenous application of NAD to transected axons. NAD applied locally to the axon resulted in delayed Wallerian degeneration, and this protection was shown to be dependent on the MEK-Erk pathway. NAD application maintained Erk phosphorylation for 24 hours, and Erk1/2 inhibition resulted in normal degeneration of NAD-treated, transected axons. Also, treatment of transected axons with the drugs; sirtinol, an inhibitor of sirtuins (which uses NAD as a substrate), and Ro-31-8220, an inhibitor of p90Rsk (a downstream target of Erk1/2), increased metabolic activity of transected axons given NAD. This work suggests the MEK/Erk1/2 pathway is important in survival of transected axons and activity-dependent survival may have therapeutic implications for neurodegenerative diseases and neural trauma.