New insights into neuronal regeneration: The role of axonal protein synthesis in pathfinding and axonal extension

Protein synthesis in dendrites has become an accepted cellular mechanism that contributes to activity-dependent responses in the post-synaptic neuron. Although it was argued that protein synthesis does not occur in axons, early studies from a number of groups provided evidence for the presence of RNAs and active protein synthesis machinery in both invertebrate and vertebrate axons. Work over the past decade has confirmed these early findings and has proven the capability of axons to locally synthesize some of their own proteins. The functional significance of this localized protein synthesis remained largely unknown until recent years. Recent studies have shown that mRNA translation in developing and mature axons plays a role in axonal growth. In developing axons, protein synthesis allows the distal axon to autonomously respond to guidance cues by rapidly changing its direction of outgrowth. In addition, local proteolysis of axonal proteins contributes axonal guidance and growth cone initiation. This local synthesis and degradation of proteins are likely to provide novel insights into how growing axons navigate through their complex environment. In mature axons, injury triggers formation of a growth cone through localized protein synthesis, and moreover, in these injured axons locally synthesized proteins provide a retrogradely transported signal that can enhance regenerative responses. The intrinsic capability for axons to autonomously regulate local protein levels can be modulated by exogenous stimuli providing opportunities for enhancing regeneration. In this review, the concept of axonal protein synthesis is discussed from a historical perspective. Further, the implications of axonal protein synthesis and proteolysis for neural repair are considered.