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Local protein synthesis, actin dynamics, and LTP …
This finding is in accordance with studies using mollusc neurons, which show that presynaptic protein synthesis is required for synapse formation,–. It is also in agreement with a study of the Drosophila melanogaster neuromuscular junction, which shows that 3-phosphoinositide-dependent protein kinase 1 (PDK1) and ribosomal protein S6 kinase (S6K) — which are both components of the mTOR pathway — control synaptic bouton size, active zone number and synaptic function, although translation-dependency has not been tested in this case. Furthermore, fragile X mental retardation protein (FMRP), a known translational regulator and mediator of synaptic plasticity in dendritic spines,, is found in axons and growth cones–, and its loss leads to a cell autonomous defect in the formation of presynaptic terminals in organotypic mouse hippocampal slices. Other translational regulators such as survival of motor neuron (SMN1), and Hu-antigen D (HUD; also known as ELAVL4), also localize to axons and growth cones, thus indicating a probable broad presynaptic role of translation in aspects of synapse formation.
In addition to regulating mTOR, guidance cues may directly regulate ribosomes. DCC (deleted in colorectal carcinoma), a netrin 1 receptor, directly binds to ribosomal protein L5, a component of the 60S ribosomal subunit. Binding of netrin 1 to DCC activates translational initiation and subsequently releases the ribosome–mRNA complex from DCC, thereby allowing more ribosomes to form polysomes in the vicinity of receptor activation. This provides a crucial mechanism for the localized control of mRNA translation near the site of signal activation and may also prevent unnecessary translation in the basal state by sequestering ribosomes. It will be of interest to determine whether other receptors show similar interactions with the translational machinery.
During Local Protein Synthesis ABSTRACT
The initial lack of interest in local axonal mRNA translation can be traced back to findings in the 1970s using the squid giant axon. It was suggested that protein synthesis is unlikely to occur in mature axons as little or no ribosomal RNA (as measured by their optical densities on polyacrylamide gels) was observed in the axoplasm. This interpretation was, however, later disputed by evidence obtained using more sensitive biochemical methods showing the presence of ribosomal RNAs, mRNAs and actively translating polysomes in squid giant axons. In mammals, ribosomes were identified by electron microscopy in embryonic cortical and sympathetic neuronal axons in cell culture, and in embryonic peripheral sensory axons in vivo. Recent immuno-electron microscopy has shown specific immunoreactivity to the ribosomal protein S6 in the axons of cultured embryonic sympathetic and hippocampal neurons. Notably, axonal ribosomes rarely form polysomes in vivo,,, unlike in culture conditions, which suggests that monosomal translation may predominate or that translational activation is spatiotemporally restricted in axons in normal conditions.
Thus, local mRNA translation can be regarded as a common mechanism for the regulation of local proteomic homeostasis in response to extracellular signals in axons and dendrites. Both developing, and mature, axons contain complex and dynamic mRNA repertoires, and recent studies have provided insights into the regulation of axonal mRNA translation. Here, we aim to provide a conceptual framework for this emerging field of active research by reviewing our understanding of the current literature and discussing future directions.
Chronic Mild Stress-Induced Alterations of Local Protein Synthesis…
The research group of Associate Professor Nobuyuki Shiina of the National Institute for Basic Biology (Laboratory of Neuronal Cell Biology) and the Okazaki Institute for Integrative Bioscience, and Professor Makio Tokunaga of the Tokyo Institute of Technology (Graduate School of Bioscience and Biotechnology) have shown, using mouse neurons, that local protein synthesis in dendrites is needed for the development of normal neuronal network architecture. The information stored in the DNA inside the nucleus of cells is taken up by messenger RNA (mRNA) and the mRNA acts as a template for protein synthesis. Normally protein synthesis occurs in the vicinity of the cellfs nucleus. A special feature of neurons, however, are the multitudes of long thin protuberances called dendrites that extend out of them; and inside these dendrites mRNA transports some genetic information far from the nucleus to perform localized protein synthesis. Knowledge of the role of this local protein synthesis had previously been limited. The research group focused on the RNG105 gene and has shown for the first time that it is essential for mRNA transport and the local protein synthesis that accompanies it in dendrites, and therefore essential for the proper formation of neural networks. The results of this research were published in the Journal of Neuroscience on September 22nd 2010.
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mRNAs can be targeted to specific neuronal subcellular domains, which enables rapid changes in the local proteome through local translation. This mRNA-based mechanism links extrinsic signals to spatially restricted cellular responses and can mediate stimulus-driven adaptive responses such as dendritic plasticity. Local mRNA translation also occurs in growing axons where it can mediate directional responses to guidance signals. Recent profiling studies have revealed that both growing and mature axons possess surprisingly complex and dynamic transcriptomes, thereby suggesting that axonal mRNA localization is highly regulated and has a role in a broad range of processes, a view that is increasingly being supported by new experimental evidence. Here, we review current knowledge on the roles and regulatory mechanisms of axonal mRNA translation and discuss emerging links to axon guidance, survival, regeneration and neurological disorders.
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Local NSAID infusion does not affect protein synthesis …
Some evidence suggests that local mRNA translation may regulate pain sensitivity. mRNAs encoding transient receptor potential cation channel subfamily V member 1 (TRPV1), a capsaicin-gated and high temperature-gated ion channel, are detected in the axons of peripheral nociceptors in adult mice. Interestingly, inflammatory insults increase the axonal transport of Trpv1 mRNA to central endings in the spinal cord, and intrathecal delivery of Trpv1 antisense oligodeoxynucleotides reduces the inflammation-induced TRPV1 hypersensitivity in spinal cord slices. Nerve injury also induces specific accumulation of tetrodotoxin-resistant voltage-gated sodium channel 1.8 (Nav1.8) mRNA in injured axons in vivo. Subcutaneous injection of Nav1.8 siRNA into areas in which peripheral endings terminate specifically reduces Nav1.8 mRNA in the axon but not in the cell body, and reduction of axonal Nav1.8 mRNA correlates with the reversal of neuropathic pain in mice. Furthermore, delivery of inhibitors of protein synthesis either intrathecally (rapamycin and cycloheximide) or intraplantarly (rapamycin and anisomycin) alleviates pathological pain in mice, although these effects may indirectly result from the decreased production and release of pro-inflammatory cytokines from neighbouring cells. The axons of cultured peripheral sensory neurons also contain mRNAs encoding KOR1, a GPCR that generates an antinociceptive signal, and the axonal localization of Kor1 mRNA is enhanced by depolarization in culture,. Direct evidence showing that these receptors are trafficked to the plasma membrane is still lacking, although these axons have functional machinery to target proteins to the cell surface and mollusc axons can target locally synthesized conopressin receptor to the plasma membrane.
synapses by local protein synthesis.
Numerous neurodevelopmental disorders, such as fragile X mental retardation and autism spectrum disorders, seem to share dysregulated protein synthesis as an underlying cause of clinical pathologies. Although dendrites are well-documented sites of synaptic pathology, there is less evidence for axons. Recent evidence, however, shows that translational regulators such as FMRP, also localize to axons and regulate presynaptic function. Therefore, dysregulated axonal mRNA translation may, in future, be found to contribute to clinical pathologies of neurodevelopmental disorders.
RNA Transport and Local Protein Synthesis in the …
In the CNS, axons lose their ability to regenerate in adulthood. Intriguingly, increasing protein synthesis might restore their regenerative potential. In mice, global translational activity (as measured by the phosphorylation of the ribosomal protein S6) in retinal ganglion cells decreases with age,. In contrast to peripheral axons, injury to postnatal retinal axons downregulates global translational activity in retinal ganglion cells in vivo. Intriguingly, genetic deletion of the negative regulators of mTOR, PTEN and tuberous sclerosis protein 1 (TSC1), prevents this decrease in translational activity. Remarkably, these rejuvenated neurons can regenerate axons, although whether axonal or somal protein synthesis plays a more important role in this effect is unknown. Thus, different translational responses to nerve injury might account for the different abilities of CNS and PNS neurons to regenerate axons.
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