Intra-axonal mechanisms driving axon regeneration

Abstract

Traumatic injury to the peripheral and central nervous systems very often causes axotomy, where an axon loses connections with its target resulting in loss of function. The axon segments distal to the injury site lose connection with the cell body and degenerate. Axotomized neurons in the periphery can spontaneously mount a regenerative response and reconnect to their denervated target tissues, though this is rarely complete in humans. In contrast, spontaneous regeneration rarely occurs after axotomy in the spinal cord and brain. Here, we concentrate on the mechanisms underlying this spontaneous regeneration in the peripheral nervous system, focusing on events initiated from the axon that support regenerative growth. We contrast this with what is known for axonal injury responses in the central nervous system. Considering the neuropathy focus of this special issue, we further draw parallels and distinctions between the injury-response mechanisms that initiate regenerative gene expression programs and those that are known to trigger axon degeneration.

Keywords: Axon regeneration; Axonal protein synthesis; Peripheral neuropathies; Retrograde signalling.

Figure 1 –. Schematic of axon intrinsic signaling mechanisms that contribute to axon regeneration.

A, Depiction of back-propagating Ca²⁺ wave and localized effects of injury-induced Ca²⁺ influx into the axon are shown on top. Ca²⁺ entry triggers a retrograde Ca²⁺-mediated/dependent axon-to-soma signal (1) and activates localized protein synthesis (2) that provides a second means for axon-to-soma signaling through protein transport (3). B, Ensuing regeneration-promoting mechanisms are depicted on the bottom, with soma-to-axon signaling through anterograde transport of mRNAs and proteins (4) with subsequent translational regulation of these axonal mRNAs. In addition to Ca²⁺ influx and release from intra-cellular stores, the extracellular environment, including non-neuronal cells resident and infiltrating into the nerve after injury (5), have the potential modulate localized translation events and mRNA transport.

Figure 2 –. Schematic of axon intrinsic signaling mechanisms that contribute to axon degeneration.

Schematic representing potential overlapping mechanisms for preventing Ca²⁺ store release from ER in mature functioning axons (top) and the loss of this mechanism with paclitaxel-induced peripheral neuropathy (Pease-Raissi et al., 2017). Axonally synthesized Bcl_w prevents or attenuates activation of IP₃R along the ER (A, 1–2). Activation of IP₃R (B, 3) was shown to be involved in degeneration Wallerian in severed axons (Villegas et al., 2014) and depletion of ER Ca²⁺ stores can trigger the UPR (Malhotra and Kaufman, 2007). As outlined in the text, UPR activation in axons is linked to some of the injury-associated translation events seen after the traumatic axonal injury depicted in Figure 1.