Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease

Abstract

Intra-axonal protein synthesis has been shown to play critical roles in both development and repair of axons. Axons provide long-range connectivity in the nervous system, and disruption of their function and/or structure is seen in several neurological diseases and disorders. Axonally synthesized proteins or losses in axonally synthesized proteins contribute to neurodegenerative diseases, neuropathic pain, viral transport, and survival of axons. Increasing sensitivity of RNA detection and quantitation coupled with methods to isolate axons to purity has shown that a surprisingly complex transcriptome exists in axons. This extends across different species, neuronal populations, and physiological conditions. These studies have helped to define the repertoire of neuronal mRNAs that can localize into axons and imply previously unrecognized functions for local translation in neurons. Here, we review the current state of transcriptomics studies of isolated axons, contrast axonal mRNA profiles between different neuronal types and growth states, and discuss how mRNA transport into and translation within axons contribute to neurological disorders.

Translational Control Mechanisms in Persistent Pain

“…mRNAs, ribosomes, and other components of translational machinery are present in PNS axonal and CNS dendritic compartments [17,35,36]. Release of endogenous molecules associated with tissue damage increases nascent protein synthesis in DRG neurons and their axons via activation of signaling pathways upstream of translation (Figure 3).…”

“…However, the identity of the full repertoire of mRNAs that are translated to lead to this change in excitability is only starting to emerge. While much of work has been done to identify mRNAs that localize to DRG axons in vitro [35], there are substantial technical challenges to confirm that these mRNAs localize to DRG axons in vivo . Nevertheless, several mRNAs have been localized to DRG axons in mice and rats, and some of these have been linked to pain hypersensitivity, such as the mRNAs for CREB, CPEB, and Na v 1.8 [38,39] (Table 2).…”

Toward Axonal System Biology: Genome Wide Views of Local mRNA Translation

“…The gene ontology (GO) analysis of the mRNAs enriched in axons compared with the soma reveals many shared GO terms (also analyzed in ref. []), including those related to translation, mitochondria, and cytoskeleton. Other categories are represented in some data sets, for example intracellular trafficking, axon guidance, and synaptic‐related proteins (Table ).…”

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

“…For some mRNAs, this localized translation imparts unique functions to the cell. As remarkably polarized cells with widely separated and specialized subcellular domains, neurons have provided a very useful model system to profile the populations of mRNAs that are transported into axons and dendrites as well as to test functions of proteins synthesized locally in these subcellular compartments (Kar et al, 2018;Terenzio et al, 2017). Indeed, axons can extend to lengths that are more than 1000-fold longer than the neuron's cell body diameter, and localized synthesis of new proteins in distal axons provides a level of autonomy to respond to extracellular stimuli (Sahoo et al, 2018).…”

“…RNA profiling studies have shown hundreds to thousands of mRNAs localized into axons of sensory, cortical, retinal ganglion cell, and motor neurons (Kar et al, 2018). These populations include several mRNAs encoding proteins that can impact the axonal cytoskeleton, either directly through generation of cytoskeletal proteins or indirectly by generation of proteins that regulate polymerization, depolymerization, severing or branching of the cytoskeleton.…”