Signaling mechanisms regulating Wallerian degeneration

Abstract

Wallerian degeneration (WD) occurs after an axon is cut or crushed and entails the disintegration and clearance of the severed axon distal to the injury site. WD was initially thought to result from the passive wasting away of the distal axonal fragment, presumably because it lacked a nutrient supply from the cell body. The discovery of the slow Wallerian degeneration (Wld(s)) mutant mouse, in which distal severed axons survive intact for weeks rather than only one to two days, radically changed our thoughts on the autonomy of axon survival. Wld(s) taught us that under some conditions the axonal compartment can survive for weeks after axotomy without a cell body. The phenotypic and molecular characterization of Wld(S) and current models for Wld(S) molecular function are reviewed herein-the mechanism(s) by which Wld(S) spares severed axons remains unresolved. However, recent studies inspired by Wld(s) have led to the identification of the first 'axon death' signaling molecules whose endogenous activities promote axon destruction during WD.

Figure 1. Wld^S protein structure

See text for details.

Figure 2. Signaling events initiated by axotomy

Nmnat2 is continuously delivered on vesicles (green) from the soma to the axon. Axotomy terminates delivery and axons survive until Nmnat2 is depleted. Influx of extracellular Ca²⁺ is activated by axotomy, which may be amplified by release from internal stores. Axonal Ca²⁺ activates calpains to drive cytoskeletal degradation, and overwhelms mitochondria, leading to loss of mitochondrial membrane potential and increased ROS production. Eventually mitochondrial undergo PTP formation and granular disintegration of the axon ensues. Inset box: genetic modulators of Wallerian degeneration, see text for details.