Abstract
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.
Highlights
Neurons use their axons to communicate with remote cells
Axonopathies are increasingly recognized as major contributors in neurological conditions, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [12], Parkinson’s disease (PD) [13], traumatic brain injury (TBI) [14], and chemotherapy-induced peripheral neuropathy (CIPN) [15]
The discovery and characterization of axon death signalling, which is activated by injury, provided exciting insights into the underlying mechanism mediating axonal self-destruction after injury
Summary
Neurons use their axons to communicate with remote cells. These axons can be extremely long, ranging from millimetres to centimetres to metres depending on the host, the type of neuron and the target cell [1,2]. Identified by and named after Augustus Waller, Wallerian degeneration (WD) is an umbrella term under which two distinct mechanisms occur [18] (figure 1): first, severed axons—separated from the soma—actively execute their own disassembly (axon death) within 1 day, through an evolutionary conserved axon death signalling cascade; and second, surrounding glial cells engage and clear the resulting debris within 3–5 days. Axon death signalling is activated when the axon is cut, crushed or stretched [21,22], it seems to be a major contributor in different animal models of neurological conditions, e.g. where axons degenerate in the absence of injury [23]. We will conclude with a brief overview of engaged axon death signalling in the diseased or injured nervous system
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