BrainPop--RNA Protein Synthesis
Protein Synthesis – Bodybuilding Brain
Protein Synthesis -Translation and Regulation
Down syndrome has also recently been linked to dysregulated local translation of CPEB-associated dendritic mRNAs. DSCAM mRNA contains several CPE sequences and is localized to dendrites, and NMDA receptor-mediated translation of DSCAM is elevated in a mouse model of Down syndrome (). In addition, BDNF protein levels and BDNF-induced local translation are elevated in this mouse model; interestingly, BDNF is also a CPE-containing mRNA that is locally translated (, , ). Moving forward it will be important to investigate whether these mRNAs are indeed locally regulated by CPEB and its associated translational regulators, and whether dysregulation of this mechanism might contribute to the altered protein expression observed in the disease model.
Synaptic activity is a spatially-limited process that requires a precise, yet dynamic, complement of proteins within the synaptic micro-domain. The maintenance and regulation of these synaptic proteins is regulated, in part, by local mRNA translation in dendrites. Protein synthesis within the postsynaptic compartment allows neurons tight spatial and temporal control of synaptic protein expression, which is critical for proper functioning of synapses and neural circuits. In this review, we discuss the identity of proteins synthesized within dendrites, the receptor-mediated mechanisms regulating their synthesis, and the possible roles for these locally synthesized proteins. We also explore how our current understanding of dendritic protein synthesis in the hippocampus can be applied to new brain regions and to understanding the pathological mechanisms underlying varied neurological diseases.
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The quest to determine if dendritic protein synthesis occurs required novel technique development. Torre and Steward cultured neurons on a porous surface through which only neurites could extend, and transected neurites were pulsed with 3H-leucine resulting in puromycin-sensitive labeling of proteins within dendrites (). Using hippocampal slices, Feig and Lipton showed that the muscarinic receptor agonist carbachol in combination with high-frequency stimulation produced a three-fold increase in 3H-leucine incorporation in CA1 neuron dendrites (). More recently, dendritic protein synthesis was visualized in cultured hippocampal neurons using local perfusion of a fluorescently-labeled non-canonical amino acid and brain-derived neurotrophic factor (BDNF) (). These elegant studies and novel technologies demonstrated that new proteins can indeed be synthesized within the dendrites of hippocampal neurons.
In this review, we discuss the seminal studies addressing several fundamental questions: 1) what is the relationship between synaptic activity and dendritic protein synthesis, 2) what mRNAs are localized to and translated within dendrites, 3) what are the molecular mechanisms that regulate activity-induced dendritic protein synthesis, and 4) does disrupted dendritic protein synthesis contribute to brain disease? We also discuss the possibility that our increasing knowledge of the basic mechanisms regulating dendritic protein synthesis at hippocampal synapses can be applied to other brain regions and, perhaps, to developing novel therapeutics for brain diseases involving disrupted synaptic protein synthesis. Local protein synthesis in the axonal compartment is important during neuronal development and regeneration; however, these topics have been extensively summarized in recent reviews and will not be discussed here (, , , ).
Where there was one cell there are two, then four, then eight,..
While recent studies have begun to reveal the contingent of localized mRNAs and the mechanisms mediating their local regulation, much work is still necessary in order to understand the function of locally synthesized proteins and the distinct physiological conditions during which specific proteins are locally synthesized. The use of novel technologies including non-canonical amino acids, local perfusion assays, and microfluidic chambers will be of the utmost importance in such studies. In addition, more work is needed to understand the multistep mechanisms involved in dendritic mRNA localization and translational regulation at synapses. Protein synthesis-dependent plasticity clearly involves multiple levels of spatio-temporal regulation, which likely proceed first by the translational de-repression of mRNAs that are already present in spines. These early responses appear to be followed by changes in the localization and dynamics of mRNAs in the nucleus, soma and dendrite. These mechanisms likely differ between mRNAs, and there appear to be a collection of important trans-acting mRNA binding proteins that regulate these steps. As discussed, a promising new direction for the local protein synthesis field is the expansion of studies to include brain regions beyond the hippocampus and cerebral cortex. Exciting new studies suggest that localized protein synthesis might occur in the amygdala, striatum, and hypothalamus, and it will be intriguing to see how widespread the role of dendritic protein synthesis is in modulating brain function and behavior. Finally, it is becoming evident that many neurological disorders might involve dysregulated protein synthesis. While intellectual disabilities and autism spectrum disorders have received some focus recently, additional studies indicate that neurodegenerative and psychiatric disorders could also involve altered synaptic proteins synthesis. Clinical research on fragile X syndrome that is based, in part, on basic studies of FMRP-mediated synaptic protein synthesis has already emerged, and this suggests that the continued study of basic mechanisms regulating localized protein synthesis is a promising means for understanding and identifying therapeutic strategies to treat neurological disorders.
Huntington’s disease is caused by a polyglutamine expansion in the gene encoding huntingtin protein, and the primary pathological manifestation is striatal medium spiny neuron degeneration (). The specific function of huntingtin is unclear but it has been implicated in many types of intracellular transport, and recent studies indicate that huntingtin might be involved in dendritic RNA transport and regulation. Huntingtin interacts with Ago2 and represses the translation of a reporter protein, and it co-localizes with Ago2, P-body proteins, and Staufen in rat cortical neuron dendrites (, ). Huntingtin was also shown to co-localize with the 3′ UTR of IP3R1, -actin, and BDNF mRNAs in dendrites (, ). Furthermore, huntingtin knockdown reduced dendritic levels of -actin mRNA, Ago2 protein, and P-bodies (, ). These studies reveal a potentially exciting advance in understanding the basic biology of dendritic mRNA regulation and identify a new putative role for dysregulation of dendritic RNA processing in Huntington’s disease. If indeed huntingtin does play a role in regulating mRNA transport and local translation, then an important next step will be to decipher why striatal neurons are specifically affected in this disease.
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The brain encodes information by transducing experience-mediated neural activity into long-term modifications of synapses. These activity-dependent alterations in synapse structure and function are generally termed synaptic plasticity. A single neuron bears as many as 104 synapses, which can be modified independently during input-specific forms of synaptic plasticity. In many cases, the long-term synaptic modifications underlying synaptic plasticity rely upon new protein synthesis. Therefore, synaptic plasticity requires precise mechanisms to deliver newly synthesized proteins to specific synapses. One means to control the synaptic protein composite is through dendritic mRNA transport and local protein synthesis at postsynaptic sites. Local synthesis of new proteins affords the neuron tight spatial and temporal control of signal-induced gene expression. While both somatic and synaptic protein synthesis are critical for neuronal function, herein, we focus on the role of local protein synthesis in the normal and diseased brain.
Institute for Protein Research, Osaka University
The overwhelming majority of studies on dendritic protein synthesis have been completed using hippocampal neurons or slices. Indeed, the hippocampus is critical for long-term memory formation, but protein synthesis-dependent synaptic plasticity occurs in many other brain regions as well (see ). Collectively, these studies have established that protein synthesis-dependent plasticity controls a variety of animal behaviors including spatial memory, motor learning, drug addiction, social and reproductive behaviors, appetitive learning, and fear conditioning. Moreover, this collection of findings underscores the critical function of protein synthesis during synaptic plasticity throughout the brain and the importance for understanding how protein synthesis controls synapse structure and function. So far, a few studies have indicated that dendritic protein synthesis might play a role in brain regions other than the hippocampus (). In particular, two studies have hinted at a role for dendritic protein synthesis in the amygdala. First, polyribosomes are present within the dendrites and spines of lateral amygdala neurons, and fear conditioning increases the number of polyribosomes within dendrites (). Secondly, mice lacking the 3′ UTR of αCaMKII showed altered fear learning in an amygdala-dependent (hippocampus-independent) conditioning paradigm, suggesting that the dendritic localization of αCaMKII in amygdala neurons is necessary for this type of learning (). However, as stated above, a caveat with this study is that it is unclear whether the severe reduction in αCaMKII protein caused the observed deficit in fear learning or whether it is truly a lack of dendritic translation. Nevertheless, the role of dendritic protein synthesis in the amygdala has been implicated by both of these studies, and these findings warrant future work investigating what transcripts are localized and translated in dendrites as well as the mechanisms regulating local protein synthesis in the amygdala.
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The loss of protein synthesis during early mouse-brain development was shown to be the result, at least in part, of the inability of microsomes obtained from more mature neural tissue to participate in rapid polypeptide synthesis. The loss of brain microsomal activity was observed shortly after birth and continued until the animals were approximately ten days old. Despite the difference in synthetic activity, sucrose gradient profiles of microsomes and polyribosomes from young and more mature brain tissue were quite similar. The loss in protein synthesis was shown to be independent of available mRNA and not attributable to aminoacyl-RNA synthetases and tRNA binding activity.
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