Axon death signalling in Wallerian degeneration among species and in disease

Axon loss is a shared feature of nervous systems being challenged in neurological disease, by chemotherapy or mechanical force. Axons take up the vast majority of the neuronal volume, thus numerous axonal intrinsic and glial extrinsic support mechanisms have evolved to promote lifelong axonal survival. Impaired support leads to axon degeneration, yet underlying intrinsic signalling cascades actively promoting the disassembly of axons remain poorly understood in any context, making the development to attenuate axon degeneration challenging. Wallerian degeneration serves as a simple model to study how axons undergo injury-induced axon degeneration (axon death). Severed axons actively execute their own destruction through an evolutionarily conserved axon death signalling cascade. This pathway is also activated in the absence of injury in diseased and challenged nervous systems. Gaining insights into mechanisms underlying axon death signalling could therefore help to define targets to block axon loss. Herein, we summarize features of axon death at the molecular and subcellular level. Recently identified and characterized mediators of axon death signalling are comprehensively discussed in detail, and commonalities and differences across species highlighted. We conclude with a summary of engaged axon death signalling in humans and animal models of neurological conditions. Thus, gaining mechanistic insights into axon death signalling broadens our understanding beyond a simple injury model. It harbours the potential to define targets for therapeutic intervention in a broad range of human axonopathies.