Regulation of Subcellular Protein Synthesis for Restoring Neural Connectivity

Abstract

Neuronal proteins synthesized locally in axons and dendrites contribute to growth, plasticity, survival, and retrograde signaling underlying these cellular processes. Advances in molecular tools to profile localized mRNAs, along with single-molecule detection approaches for RNAs and proteins, have significantly expanded our understanding of the diverse proteins produced in subcellular compartments. These investigations have also uncovered key molecular mechanisms that regulate mRNA transport, storage, stability, and translation within neurons. The long distances that axons extend render their processes vulnerable, especially when injury necessitates regeneration to restore connectivity. Localized mRNA translation in axons helps initiate and sustain axon regeneration in the peripheral nervous system and promotes axon growth in the central nervous system. Recent and ongoing studies suggest that axonal RNA transport, storage, and stability mechanisms represent promising targets for enhancing regenerative capacity. Here, we summarize critical post-transcriptional regulatory mechanisms, emphasizing translation in the axonal compartment and highlighting potential strategies for the development of new regeneration-promoting therapeutics.

Keywords: RNA stability RNA-binding protein; RNA transport; integrated stress response; protein synthesis.

Figure 1

Leveraging localized translation for developing neural repair therapeutics. Schematic of a neuron illustrating the key molecular determinants that regulate the specificity, timing, and levels of protein synthesis from localized mRNAs. These determinants include mRNA transport and stability, granule dynamics, ribosome recruitment, and translation initiation. Therapeutic strategies that target these mechanisms to enhance axon regeneration are summarized in the accompanying table, along with their corresponding molecular targets and approaches. For example, the DNA aptamer AS1411 disrupts the interaction between nucleolin and the kinesin motor protein KIF5A, impairing axonal mRNA transport and offering a targeted means of modulating transcript localization. A G3BP1-derived peptide promotes stress granule disassembly by lowering the threshold for liquid–liquid phase separation, thereby enhancing local translation. Additionally, targeting the RNA-binding protein KHSRP through protein depletion reduces its promotion of mRNA decay, stabilizing growth-associated transcripts and enhancing their translation in regenerating axons. Together, these strategies exemplify how manipulation of localized translational pathways can be harnessed to promote neuronal repair.