Axon death signalling in Wallerian degeneration among species and in disease

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.

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…The full mechanism of cytotoxicity in the axon is unclear. However, in the case of neuron-autonomous Wallerian degeneration, the late-phase Ca 2+ elevation and subsequent calpain activation required for microtubule destabilization is gated by a metabolic signaling cascade involving depletion of nicotinamide adenine dinucleotide (NAD + ), activation of Sterile-alpha and armadillo motif containing protein (SARM) and C-Jun N-terminal kinase (JNK) (Llobet Rosell and Neukomm, 2019). Although caspase 3 is a major target of granzyme B protease activity (Adrain et al, 2005), its role in cytotoxic axon degeneration remains unclear.…”

“…This may occur either from disconnection of nerve branches from their peripheral target by physical injury (Bennett and Xie, 1988;Seltzer et al, 1990;Kim and Chung, 1992;Decosterd and Woolf, 2000) or a dying-back of axons from their terminals due to metabolic (O'Brien et al, 2014) or chemical neurotoxicity (Hoke and Ray, 2014). Axonal loss after injury is characterized by the mechanisms of Wallerian degeneration: a neuron-autonomous (i.e., self-determined) process involving active metabolic signaling within the axon leading to cytoskeletal destabilization and fragmentation (Gerdts et al, 2016;Llobet Rosell and Neukomm, 2019). Additionally, dying back of axons utilizes apoptotic pathways, while protecting the cell body from death (Yaron and Schuldiner, 2016).…”

Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

“…Axon degeneration is an early feature of most neuronal injuries and is a primary cause of functional impairment. The degeneration of axons distal to a lesion site is highly stereotyped and is known as Wallerian degeneration [17,18]. In this process, the distal part of an axon first experiences a latent phase.…”

Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster

“…In Drosophila Melanogaster, only one isoform of NMNAT is present, this is called dNMNAT (drosophila NMNAT) and serves the functions of mammalian NMNAT 1-3 isoforms, including delay in Wallerian degeneration. NMNAT proteins are evolutionarily conserved and dNMNAT can directly substitute for NMNAT isoforms in mammalian systems (24)(25)(26)(27)(28).…”