The role of local protein synthesis and degradation in axon regeneration

Abstract

In axotomised regenerating axons, the first step toward successful regeneration is the formation of a growth cone. This requires a variety of dynamic morphological and biochemical changes in the axon, including the appearance of many new cytoskeletal, cell surface and signalling molecules. These changes suggest the activation of coordinated complex cellular processes. A recent development has been the demonstration that the regenerative ability of some axons depends on their capacity to locally synthesise new proteins and degrade others at the injury site autonomously from the cell body. There are also events involving the degradation of cytoskeletal and other molecules, and activation of signalling pathways, with axotomy-induced calcium changes probably being an initiating event. A future challenge will be to understand how this complex network of processes interacts in order to find therapeutic ways of promoting the regeneration of CNS axons.

Fig. 1

(A) Inside a healthy axon, a variety of protein synthesis and degradation machinery is present. (B) As a result of transection, the axon is divided into two parts. The distal portion undergoes Wallerian degeneration and will subsequently be degraded. In the proximal portion, calcium enters the axon due to the disruption to the plasma membrane, as well as via voltage-gated calcium channels. Cytoskeletal structures such as microtubules and neurofilament undergo depolymerisation and degradation. Neurotrophins from extracellular sources may also help the localisation of mRNAs. (C) Later on, a terminal swelling appears at the tip of the proximal stump, as regeneration ensues. Microtubules and neurofilaments undergo re-polymerisation. Protein synthesis and protein degradation occur simultaneously within the axon. Protein synthesis takes place via a mechanism dependent on mTOR, ERK 1/2 and PKA. Examples of proteins synthesised locally after an injury include importin b1, vimentin, ribosomal protein L4 etc. Protein degradation may occur via calpain-dependent proteolysis (e.g. vimentin, spectrin) or ubiquitin–proteasome system, while the role of autophagy remains to be elucidated.