Translation in Neurons
Adam Evans
Defining Translation
Once a set of genetic instructions coded in DNA has been transcribed, it exits the nucleus through nuclear pores and into the cytoplasm as mRNA. It is here where the mRNA passes through a pseudo-organelle called the ribosome. The ribosome effectively holds the mRNA steady and orients it in such a way that it can be translated by tRNA (which, ironically, stands for transfer RNA, not translation RNA). This process, called translation, is how our genetic instructions are converted into proteins.
Each tRNA molecule has an anticodon that corresponds to the codons written into the mRNA. When a tRNA molecule finds a match, it deposits the appropriate amino acid, coded for by each codon. Enzymes in the ribosome itself catalyze the formation of peptide bonds between the amino acids, causing them to form a peptide chain. The completed chain, now a polypeptide, can then be folded and assembled into a functional protein following translation.
Three Steps of Translation:
- Initiation: The start codon at the beginning of the mRNA binds to the ribosome, which orients it so that it is ready to be read; first tRNA molecule binds
- Elongation: The mRNA continues to move through the ribosome, with tRNA molecules depositing the correct amino acids in order to form a peptide chain
- Termination: A stop codon at the end of the mRNA enters the ribosome; tRNA stops binding and the finished polypeptide is released into the ribosome, ready to be folded
This is the process of translation that all human cells–and all cells of all life on Earth, for that matter–follow in protein synthesis. This includes neurons; however, given the unusual time sensitivity and metabolic demands of even the most mundane tasks of the neuron, natural selection has required them to execute the process of translation more creatively.
Localized Translation
Ordinary animal cells can get by with protein synthesis occurring away from where they are needed, content to wait around for the proteins to be transported after they are built, folded, and packaged at a distant location. Furthermore, their generally compact shapes make protein transfer between subcellular locations rather efficient. Neurons, on the other hand, don’t have such precious time to waste. With long distal projections and highly time-sensitive jobs, neurons utilize localized translation to ensure that the necessary proteins are where they need to be, when they need to be.
Clustered presence of translational machinery outside of neuronal somata was first observed by Steward and Levy in 1982. This seminal finding suggested that neuronal projections (in this case, rat dendrites) were capable of synthesizing proteins on-site, disrupting the long-standing assumption that they were dependent upon highly targeted transport of proteins already synthesized in the soma. While initially controversial, the concept of localized translation is now widely accepted by neuroscientists.
Functional Importance of Localized Translation in Neurons
Imagine you work at an upscale gourmet coffee shop where you receive an average of 100 orders per second from very impatient customers who expect to be served within just a few milliseconds. Unfortunately, there’s no espresso machine behind your counter, making you dependent on the nearest coffee factory to deliver all of the drinks you need to serve the customers in a timely manner. Furthermore, the nearest coffee factory is hundreds of miles away from your coffee shop, and the commute is highly unpredictable (and often dangerous).
If you have a pretty good idea of (a) how much coffee you go through during a typical day at work and (b) how quickly the trucks can get to you, you might be able to strike a deal with the factory, ensuring routine deliveries of the right amount of coffee at the right time. While this might usually work out, it can easily give rise to a few issues down the line: What if there’s a rush, and you don’t have enough coffee for all of your customers? What if work is slow for a while, and most of that expensive gourmet coffee goes bad before you can sell it? What if the coffee truck gets the wrong address, gets lost in transit, or even crashes, completely destroying the coffee? At this point, you might be thinking, why don’t I just get my own espresso machine?
This scenario represents the dilemma of neurons, who can’t always afford the gamble that comes with dependence on timely imports of pre-assembled proteins from the soma. Human motor neurons, for example, can be recruited to fire at a rate of over 200 Hz. With projections as long as one meter, even a non-stop, full-speed delivery can take upwards of ten days. These conditions especially pose a great challenge to punctual, on-demand protein delivery. In our “coffee shop” scenario, distal projections having ribosomes would be like our coffee shop getting an espresso machine; local ribosomes let them have the proteins they need, the moment they need them.
Apart from these time constraints, protein transport is extremely expensive compared to mRNA transport. It is also incredibly risky, especially through crowded cytoplasmic environments (pictured left). Ensuring safe transport of proteins is an enormous biological task for all cells. With mind to our “coffee shop” scenario, consider the price difference between getting coffee from Starbucks with DoorDash (like shipping in a pre-made protein from the soma) and making it at home with beans purchased in bulk (like locally translating proteins in the neuronal projections). Buying Starbucks is far more expensive: in part, due to shipping costs.
Locally translating a portion of their proteins, rather than solely relying on long-distance transport, saves neurons valuable energy and resources–especially with their distinctively high metabolic requirements in mind. It also saves them precious time in handling their urgent demands. With some human neurons reaching peak firing rates of over 600 Hz, sparing the extra time and resources to import proteins crucial to pre- and postsynaptic function is not an option.
Localized Translation in Dendrites
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Congue mauris rhoncus aenean vel elit. Adipiscing tristique risus nec feugiat in fermentum. Congue eu consequat ac felis donec et odio pellentesque. Viverra mauris in aliquam sem fringilla ut morbi tincidunt augue. Purus viverra accumsan in nisl nisi scelerisque eu. Eleifend donec pretium vulputate sapien nec sagittis aliquam. Magnis dis parturient montes nascetur ridiculus mus mauris vitae ultricies. Libero volutpat sed cras ornare arcu dui vivamus arcu felis. Maecenas accumsan lacus vel facilisis. In est ante in nibh mauris cursus mattis. Sit amet nulla facilisi morbi tempus iaculis urna id volutpat. Aliquam ut porttitor leo a. Libero nunc consequat interdum varius sit. Nisl purus in mollis nunc. Montes nascetur ridiculus mus mauris vitae.
Localized Translation in Axons
During development of the nervous system, localized translation within axons is common and essential in virtually every aspect of axonal development, particularly in the upkeep and function of axonal growth cones.[1,2] This provides easy access to proteins that promote synaptogenesis. However, after pruning has occurred and synaptogenesis has occurred, translational machinery in axons quickly and dramatically decreases, often to nearly undetectable levels.
Growth cones: The tips of developing axons and dendrites that guide them toward each other as they begin to form synaptic connections
Microscopic observations from the 1950s and 60s have largely shown a lack of any ribosomes within the mature axon whatsoever. Despite random sightings of mature axonal ribosomes within the same time period, neuroscientists have operated under the presumption that mature axons lacked the capacity to locally synthesize proteins for over 50 years. More recent publications have disrupted this canon, suggesting that mature axons in both invertebrate and vertebrate species are indeed capable of local protein synthesis. In fact, it has been observed in mice that over 75% of presynaptic terminals contain translational machinery. Furthermore, 40% are actively translating proteins at any given moment (lagging behind postsynaptic terminals, of which 60% are actively translating at a given moment).
Within the peripheral nervous system, ribosomes are frequently found within the axons of mature neurons that have sustained injury. It appears that these ribosomes are donated by Schwann cells and aid in and restoring axonal length and connectivity. Within the central nervous system, it has been proposed that localized translation within CNS axons is crucial to long-term maintenance and function.
While the subject of localized translation within mature axons remains a topic of controversy, contributions to the literature over the past two decades have reflected a growing curiosity in the subject. Despite the publication of increasingly compelling evidence that mature axons are, in fact, capable of local protein synthesis, the number of answers we’ve uncovered doesn’t hold a candle to the number of questions and doubts we still face (particularly in respect to the CNS). All things considered, recent findings cautiously point us toward localized translation in the mature axon as, if nothing else, a strong possibility.
Nuclear pore: A protein-lined channel in the nuclear envelope that selectively regulates movement of molecules between the nucleus and cytoplasm
RBPs: RNA-binding proteins; bind to RNA to regulate gene expression. For example,
mRNP complex: A single mRNA molecule bound by several RBPs; the basic functional unit regulating mRNA processing, export, localization, translation, and degradation
Granule: A large, transportable aggregate of mRNP complexes
mRNA Transport mechanisms
Like in any other cell, mRNA first emerges from nuclear pores and into the surrounding cytoplasm. In order to be translated locally in the dendrites or axon, it must first be transported there. Compared to the extravagant metabolic costs of protein transport, shipping mRNA across the cell is relatively cheap. Trafficking proteins across long distances can pose a risk to the integrity of the proteins themselves, even at low quantities, and mitigating this risk can be rather costly to the cell.
During transport, proteins must be escorted by chaperone proteins to prevent misfolding, repair lapses in correct folding, and prevent and break up protein aggregates. These dangers are especially present when travelling through crowded cytoplasmic environments, such as the one previously pictured. Furthermore, they must be packaged into sophisticated vesicles preceding transport, which are very expensive for the cell to synthesize and maintain. Combined with the
First, mRNA is bound by a series of RBPs that tag them for transport to their final destination (e.g., a certain dendrite), forming an mRNP complex. Then, they must be packaged into granules. Like in the transport of protein-carrying vesicles, the granule is carried to its destination by motor proteins, including kinesin (pictured) and dynein, along longitudinal tracks of structural proteins. These proteins and their role in retrograde and anterograde transport are discussed in greater detail in a later chapter.
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Regulated Translation and Synaptic Plasticity
It was first demonstrated over 50 years ago that the formation of memories in mammals requires protein synthesis, and hypothesized a further 25 years earlier. This is true for both LTP and LTD, both crucial mechanisms in long-term memory consolidation. Both of these processes are marked by stimulus-dependent synthesis and use of unique proteins, implying that the translation of relevant mRNA is tightly regulated.
Certain RBPs
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Repression of mRNA Degradation
[UNDER CONSTRUCTION]
Touch on poly(A) tails
- Shortened poly(A) tail length –> mRNA degradation (?)
- IIRC due to reduced binding affinity w/ ribosomes [RESEARCH]
- Repressed mRNA shorter tails?
- Some protein marks/freezes the tails? Maybe find specific one(s)?
Touch on cap-binding proteins?
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pulvinar etiam non quam lacus suspendisse. A cras semper auctor neque vitae tempus quam pellentesque. Nisl condimentum id venenatis a condimentum vitae sapien pellentesque habitant. Dolor morbi non arcu risus quis. Est ante in nibh mauris cursus mattis molestie a iaculis. Cursus euismod quis viverra nibh cras pulvinar mattis nunc sed. Sodales ut eu sem integer vitae. Elementum pulvinar etiam non quam lacus suspendisse faucibus interdum. Turpis egestas pretium aenean pharetra magna. Et malesuada fames ac turpis egestas maecenas pharetra.
Congue mauris rhoncus aenean vel elit. Adipiscing tristique risus nec feugiat in fermentum. Congue eu consequat ac felis donec et odio pellentesque. Viverra mauris in aliquam sem fringilla ut morbi tincidunt augue. Purus viverra accumsan in nisl nisi scelerisque eu. Eleifend donec pretium vulputate sapien nec sagittis aliquam. Magnis dis parturient montes nascetur ridiculus mus mauris vitae ultricies. Libero volutpat sed cras ornare arcu dui vivamus arcu felis. Maecenas accumsan lacus vel facilisis. In est ante in nibh mauris cursus mattis. Sit amet nulla facilisi morbi tempus iaculis urna id volutpat. Aliquam ut porttitor leo a. Libero nunc consequat interdum varius sit. Nisl purus in mollis nunc. Montes nascetur ridiculus mus mauris vitae.