RNA transport and localized protein synthesis in neurological disorders and neural repair

Abstract

Neural cells are able to finely tune gene expression through post-transcriptional mechanisms. Localization of mRNAs to subcellular regions has been detected in neurons, oligodendrocytes, and astrocytes providing these domains with a locally renewable source of proteins. Protein synthesis in dendrites has most frequently been associated with synaptic plasticity, while axonally synthesized proteins appear to facilitate pathfinding and injury responses. For oligodendrocytes, mRNAs encoding several proteins for myelin formation are locally generated suggesting that this mechanism assists in myelination. Astrocytic processes have not been well studied but localization of GFAP mRNA has been demonstrated. Both RNA transport and localized translation are regulated processes. RNA transport appears to be highly selective and, at least in part, the destiny of individual mRNAs is determined in the nucleus. RNA-protein and protein-protein interactions determine which mRNAs are targeted to subcellular regions. Several RNA binding proteins that drive mRNA localization have also been shown to repress translation during transport. Activity of the translational machinery is also regulated in distal neural cell processes. Clinically, disruption of mRNA localization and/or localized mRNA translation may contribute to pathophysiology of fragile X mental retardation and spinal muscular atrophy. Axonal injury has been shown to activate localized protein synthesis, providing both a means to initiate regeneration and retrogradely signal injury to the cell body. Decreased capacity to transport mRNAs and translational machinery into distal processes could jeopardize the ability to respond to injury or local stimuli within axons and dendrites.

Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves

“…Protein synthesis plays a critical role in both injury signaling (16,(35)(36)(37) and the formation of new growth cones during regeneration (38). Several proteins translated in peripheral neurons after injury, including vimentin and importin ␤, have been shown to be critical for regeneration (16).…”

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

“…Because all of the necessary molecular components for protein translation exist in peripheral axons (55,56), the accumulated axonal NaV1.8 mRNA may, in part, contribute to the increased functional expression of NaV1.8 in the injured nerve. The present study further demonstrated that injection of shRNA3 achieved a normalization of SNE-induced NaV1.8 mRNA in the nerve during the time (Fig.…”

RNG105 Deficiency Impairs the Dendritic Localization of mRNAs for Na+/K+ATPase Subunit Isoforms and Leads to the Degeneration of Neuronal Networks

“…Transport of mRNAs and local control of translation in neuronal dendrites are important cellular mechanisms of long-lasting synaptic plasticity and memory (Martin et al, 2000;Sutton and Schuman, 2006;Bramham and Wells, 2007), and the loss of these control mechanisms is implicated in neuronal disorders (Bassell and Kelic, 2004;Wang et al, 2007). Several mechanisms control local translation, using eIF4E-binding proteins, eEF2, the fragile X mental retardation protein (FMRP), and micro-RNAs (Jin et al, 2004;Kelleher et al, 2004;Klann and Dever, 2004;Kindler et al, 2005).…”