The Very Intelligent Protein mTOR

The Very Intelligent Protein mTOR 1

How can one protein molecule function as if it is a brain? It is able to monitor a large amount of different external and internal information and use this data to make critical decisions and take many simultaneous actions. The decisions involve multiple pathways controlling cellular growth and the amount of protein manufacturing; actions include triggering specific genetic networks for many different tasks including balancing of basic metabolism and energy production. It is hard to believe one molecule—the very intelligent protein mTOR—can perform so many different critical functions that integrate so much information related to a cell or an organism’s relation to its environment.
Because it’s effects are so vital for survival of the cell and the organism, many different diseases are related to mTOR dysfunction, such as diabetes, cancer, tumors, epilepsy, degenerative brain disorders, depression and autism. While behaving like a brain itself, mTOR has critical functions throughout the human brain.
Major accomplishments of mTOR are directly regulating the function of the ribosome, the amount of proteins made, the amount of RNA made from DNA (transcription), energy metabolism, the creation and maintenance of many different organelles and programming cellular death. mTOR is, also, directly involved in brain functions of all types, such as stimulating neural stem cells to populate the developing brain, creation of neuronal circuits, neuroplasticity and very specific functions of sleep, eating, and circadian clocks.

mTOR Stands for Mammalian Target Of Rapamycin
The strange name of this vastly complex vital protein is derived from where an antibiotic rapamycin was first found in a microbe on Easter Island in the Pacific ocean—locally Easter Island is called Rapa Nui, hence rapamycin. The mechanism of action of rapamycin was found to block a protein, which was called “mammalian target of rapamycin” or mTOR. Rapamycin was found to stop the fungus cell division cycle. It, also, stops this same division cycle in human B-lymphocytes and is now used to suppress the immune system after transplants. Later, it was found that it did a lot more.
mTOR is the critical mediator of many different pathways and signals and the very important functions of making proteins and regulating nutrients and energy. It integrates many critical inputs, such as insulin, growth factors, amino acids, oxygen and general energy levels. As a result, it is, also critical in many diseases such as diabetes, obesity, depression, cancers and brain diseases.
Rapamycin forms a large complex, which binds to a part of mTOR and decreases its activity. There are, in fact, two different mTOR Complexes—mTORC1 and mTORC2—which operate both independently of each other and together. They are often found in different cellular compartments, but work together for many different functions.
mTOR is the molecule activating, regulating and inhibiting the functions of the two large complexes. Both complexes 1 and 2 consist of a structure of many large proteins and aid in the many functions of stimulating and inhibiting the most important pathways and cascades in the cell. Rapamycin’s action is to block a particular protein only when this special protein is connected to the complexes. Rapamycin acts differently in the two complexes.

Two Interacting Large Complexes
mTOR Complex 1 (mTORC1) senses nutrients, energy and oxidation pathways and controls the manufacture of proteins with messengerRNA and ribosomes. For many years it was known that the amino acid leucine stimulated mTOR and it was thought that leucine was the critical signal for all amino acids, for example in starvation of calorie restriction experiments. But, recently a completely different second mechanism has been found for the amino acid glutamine, which opens the question of whether mTOR, in fact, responds to many other amino acids, but the mechanisms are not known. Since it is very difficult to study metabolic pathways (see post on lipid metabolism, Cannabinoids), the many ways that mTOR senses nutrients is only now being discovered. mTOR is, also, stimulated by insulin, growth factors, blood factors, phosphatidic acids and oxidative processes.
mTOR Complex 2 (mTORC2) is composed many different, equally complex proteins. This is known to regulate the cytoskeleton of the cell. It stimulates the addition of high-energy phosphate particles to proteins and many other molecules for important metabolic functions. Regulation of the cell scaffolding, and therefore its shape in building axons and dendrites, is through the action of actin. mTOR’s regulation of actin is, also, related to programmed cell death and cell survival.
mTOR1 is critically related to the function of ribosomes and ribosomes are necessary to activate the second complex. The first complex stimulates building of a ribosome, which activates the second complex. The many interactions of the two complexes make study even more difficult.

Activation of mTOR
The activation of mTOR is very complex, stimulated by a wide variety of factors. The molecules that stimulate mTOR have many hard-to-remember names that are simplified as acronyms with capital letters. These names are not intuitive, but based on how they were first discovered. They are difficult to remember because they are not related to the complex ways they interact to perform functions that have been recently learned. The way they function is based on their complex shape as with other large proteins 
A variety of powerful neurotrophic factors stimulate mTOR pathways including glutamate, special guidance molecules, the well known BDNF (brain derived neurotrophic factor), IGF1 (insulin like growth factor), VEGF vascular endothelial growth factor) and CNTF (cilliary neurotrophic factor).
Another powerful signal is Rheb that is suppressed by many different other factors including TSH (tuberous sclerosis complexes -1 and 2). TSH, itself, is highly regulated by multiple cascades with many important well-known kinases (ERK, AKT, GSK, Wnt). These various pathways stimulate mTOR is various ways, both increasing and decreasing different activity.
There are many different mechanisms to regulate mTOR. Some of these pathways relate to the use of energy in the cell, where more or less is needed at different times and places. mTOR will trigger or suppress metabolic cycles to accomplish these goals.

Amino Acid Sensing
It was thought that a specific amino acid leucine was the most important sensor for mTOR among amino acids. Recent dramatic research findings demonstrate that the mechanisms for this protein to sense the amount of two different amino acids are entirely different. They not only have different mechanisms, but the mechanisms are in different cell compartments. Yet, they both interact with the “growth regulatory complex” of the cell.
Sensing the amount of different nutrients available is highly linked to the metabolic processes that make large important molecules for the cell to grow and multiply. There are special systems of receptors that signal to mTOR through the vital sphosphoinositide-3-kinase (PI3K) cascade. There are multiple enzymes that communicate with mTOR to signal that there are enough amino acids present.
The lysosome organelle (usually thought of as a large membrane sac that breaks down large molecules and microbes) is part of this mTOR activation for amino acid sensing. A super-complex on the lysosome’s membrane surface is where mTOR is activated. Since lysosomes take apart large molecules, it is possible that mTOR monitors a pool of amino acid materials in the lysosome. Four hundred genes in humans make protein carriers for the lysosome membrane to transport many different substances, including ions, into the lysosome. Amino acid transporters are just now being identified. It is not yet clear how many different mechanisms there are for different nutrients.

Many Factors Stimulate mTOR
One of mTORs very important functions is regulating the translation of messenger RNA into proteins at the ribosome. A series of enzymes are involved in this function. The cap of the messenger RNA (methylated guanosine repeat at 5’ end of the DNA) is affected by enzymes that start the process of making proteins. Several factors compete in this process through mTOR.
A series of molecules controlled by mTOR are transcription factors. Transcription factors are proteins that bind to specific places in the DNA triggering the start and stop of the process that will make proteins. Transcription factors can promote or activate (promoters and activators) or stop (repressors) and they, also, attract the important enzyme that transfers code form DNA to messenger RNA—RNA polymerase.
An important group of mTOR factors are primarily involved in regulating the use of lipids for energy in the cell. These factors are involved in sensing lipid nutrients and regulate the myelination of axons, and the production of the neuronal action spikes in the neuron’s membrane. They are, also, related to several neurodegenerative diseases.
mTOR responds to the lack of oxygen in the cell by controlling the DNA and ribosomes that make a particular protein transcription factor regulating the response to low oxygen. These factors shift metabolism from oxidative to glycolysis pathways. This same mechanism is, also, involved to making more blood vessels when low oxygen is caused by a stroke or other damage causing low blood to tissue.
mTOR activates another factor through complex mechanisms that affect mitochondria function. In fact, blocking mTOR can create many different problems that occur in mitochondria.

mTOR Controls Autophagy
Autophagy is a complex process that a cell uses to recycle its material. It takes apart amino acids, large molecules and dysfunctional organelles. mTOR inhibition triggers autophagy, which is related to many degenerative diseases and cancer. (see post Inverse Relationship of Cancer and Brain Disease).
Autophagy in the brain is not well understood, but it has very important functions. For example, altering the pathway through mTOR causes movement disorders, destruction of neuronal axons, a particular ubuiquitin tagging of important proteins and possible death. These mTOR related problems are related to mis-folded proteins that are the hallmark of brain disease.
It is now known that autophagy is very involved in the creation of dendrite spines and their elimination when not needed. This may be the way mTOR is involved in the social behavior of the organism. Importantly, it is found that autophagy in neurons is unique with several distinct opposing mTOR pathways for inhibition and stimulation. Therefore, in the brain mTOR is a vital point of regulation.

mTOR Signaling is Vital in The Brain
In animal experiments, alteration of mTOR in the fetus eliminates many crucial regions in the developing brain. Without mTOR, the neuronal stem cells don’t produce enough neurons. In fact, mTOR appears to be critical to create the windows of brain development seen in babies.
But, this effect when exaggerated in research goes both ways both stopping neuron production and overproducing neurons. When the molecules that regulate mTOR are not present, excessive signals can dramatically change brain structure—multiple axons on neurons and alterations of dendrite structure, with increased size but fewer spines.
In the brain it has been difficult to distinguish the effects of mTOR 1 and 2. Altering either created smaller abnormal brains. In disease, mTOR 1 might have a greater effect on myelin than 2, but they clearly operate together in regulating the lipids for myelin.
mTOR takes part in the signaling between different types of cells such as astrocytes and neurons.
cells and radial gliaWhen mTOR was disrupted in research it altered visual circuits. This occurs through an unusual mechanism, where mTOR affects the guidance molecules for axon travel. In order for axons to travel to regions far away from the neuron’s cell body, the axon responds to cues along the way. These cues interact with mTOR pathways producing local stimulation of ribosomes and manufacturing proteins that are needed in particular places for the growth and direction of the axon.
Research is now focusing on identifying critical RNAs for axon growth and creation of synapses. The synapse needs a tremendous amount of local production of highly specialized molecules. While the messenger RNA comes all the way from the nucleus, the ribosomes, transfer RNAs and protein factors are right at the synapse. It is mTOR that stimulates this entire process.
There are many other ways that mTOR is regulated in its vast activity in the brain that goes beyond the already described response to the neuron’s behavior in growing axons and specific neuronal factors.

There is evidence that immune systems interact with mTOR in creating neuronal circuits. One example occurs in situations where insulin is involved in regulating synapses and uses MHC immune molecules (major histocompatibility molecules – see post).
During brain injury or spinal cord injury, where neurons are broken, mTOR uses  B0007285 Human brain cellsprocesses that were originally utilized in the developing fetal brain. These processes are reintroduced to stimulate axon growth and local production of proteins.
Ketamine triggers glutamate NMDA receptors stimulating mTOR, which increases critical proteins at the synapse and dendrite spines.
mTOR regulates the potassium channels in the dendrites, critical to the neurons electrical signal.
All of these activities of mTOR are involved in the creation of the specific brain neuronal circuits.
mTOR In Neuroplasticity Learning and Memory

First it was learned that rapamycin stopped strengthening of synapses for neuroplasticity by stopping production of critical proteins. Later, it was found that like all actions of mTOR there are many different interacting pathways. The receptor 1 is linked to the form of neuroplasticity called long-term depression—a decrease in the strength of a synapse (as opposed to long term potentiation).

When glutamate mGluRs receptors are triggered, they stimulate mTOR and increase proteins at the synapse to make it stronger in long term potentiation. Blocking mTOR stops this learning. mTORC2 then regulates the actin cytoskeleton, critical to the growing axons, dendrites and synapses.

Alterations in mTOR pathways have produced hippocampus deficits in animals, as well as decreased learning and abnormal fear conditioning and spatial learning. In fact, any change in the mTOR pathways can have dramatic effects on all types of learning and cognitive behavior. It appears that mTOR is the center of many interactive pathways that have dramatic positive and negative effects on synapses, neuronal circuits and behavior.

mTOR in Energy Regulation
PD circadian pictureThe very complex regulation of cellular energy allocation is critically involved in the monitoring of all types of different nutrients and the specific needs of different cells involved in growth and all other types of energy usage. Energy needs, also, are related to the activity and motivation of the organism. mTOR is at the center of all of this.
mTOR is very involved in the extremely complex regulation of eating. There are many different pathways involved in appetite but two primary opposite ones are in the hypothalamus using different cells producing opposing neurotransmitters and peptides. mTOR is involved in both increased eating with obesity and decreased eating with starvation. Leptin is a critical signal when full. This signal is through mTOR to produce special molecules and growth and to stop eating. mTOR appears to be critical to the anti aging effects of calorie restriction.
mTOR is critically involved in circadian rhythms. Triggering gene networks and specific protein production regulates rhythms. But, the exact mechanisms are just being discovered. Although it is not known exactly how the extremely complex and varied actions of mTOR regulate circadian rhythms, it is clearly related to the creation of special proteins for synapses that have profound effects on sleep. It is known that the learning that increases in sleep is meditated by mTOR neuroplasticity.

Diseases Caused by Alterations in mTOR
It is natural that such complex pathways would be significant in many different diseases. A full discussion is not possible in this post. Through a wide range of different pathways and defects, mTOR is involved in tuberous sclerosis, some forms of severe autism, neurofibromatosis, Fragile X syndrome, epilepsy, Alzheimer’s, Parkinson’s, Huntington’s, depression, schizophrenia and many tumors.
Reactive oxygen decreases high-energy phosphates in mitochondria and inhibits B0003650 Three mitochondria surrounded by cytoplasmthe mTOR pathway decreasing manufacture of proteins by stopping ribosomes. Without high-energy phosphates many different cascades cannot occur. Altering mTORC1 stops mitochondria respiration and production of energy.
In tuberous sclerosis, abnormal pathways produce abnormal neurons and large glia. A similar lesion is involved in many other tumors.
There are several diseases related to mTOR abnormalities that produce symptoms of autism as part of a larger picture. One particular genetic abnormality related to mTOR, estimated to cause 1 to 5% of autism, is involved with regulation of messenger RNA.
In several of the genetic mTOR tumor diseases, seizures are a prominent feature. Many of these diseases respond to treatment with rapamycin by preventing seizures and stopping them when they occur. mTOR actions in seizures might be related to its critical functions in migration of neurons and axons, production of axons and dendrites and regulalation of the electrical spikes.
There are many different vital factors that trigger mTOR pathways such as lack of oxygen, inflammation and the electrical events in neurons. These can interact with genetic defects in the very complex pathways.
Because mTOR is the most important measure of nutrients and energy needs, it can, also, be related to aging. (See post Can Cells Decide not to Age). Although, the mechanism is not known in animals, rapamycin increases life span. It, also, appears to be involved in the mechanism where calorie restriction increases life span, probably through the control of protein manufacturing.

mTOR signaling is associated with both increased amyloid andAlzheimer abnormal tau which makes neurofibrillary tangles in Alzheimer’s. Lowering mTOR signals lowers both. mTOR’s relation to autophagy is critical for the elimination of the mis-folded amyloid and tau. Parkinson’s is related to mis-folded proteins. Rapamycin increased autophagy and decreased the Parkinson abnormal alpha-synuclein proteins. Huntington’s has abnormal protein clumps. Both autophagy and mTOR are related to these increases as well. The rapid, but temporary, improvement in depression with ketamine (a glutamate NMDA antagonist) is based on mTOR pathways. Also, rapamycin blocks this effect. One gene that has been associated with schizophrenia is related to mTOR pathways. The Very Intelligent Protein mTOR

Molecular model of a ribosomeHow can one molecule be a sensor for many different nutrients, oxygen, energy, and then control protein synthesis and help remodel the brain? Many posts have marveled at cells, including microbes, behaving as if they have a brains by integrating many senses and then making many different decisions at the same time. Other posts have demonstrated the very unusual behavior of viruses having only a handful of genes and proteins, but being able to perform hundreds of complex behaviors, while tricking very advanced vastly larger human immune cells. Observing viruses, jumping genes and prions the question has to be raised about the mind interacting with these individual molecules.
But, how can one molecule behave as if it is a brain by itself, performing the same feats as the microbe—analyzing many different sensory inputs and making many simultaneous complex decisions and actions? How can the evolution of this molecule be explained, when so many interlocking different processes depend upon its exact structure?
How can anyone say that mTOR is not an extremely intelligent molecule?



1. http://jonlieffmd.com/blog/intelligent-protein-mtor

TALKING MOLECULES? THE CASE FOR mTOR
IS IT POSSIBLE that a molecule can converse like cells and organelles? A nutrient-sensing enzyme, called mTOR, has wide-ranging effects on cell processes related to growth. This molecule forms two large multiprotein complexes that receive messages about varied cellular activities and respond to all of them, simultaneously. These signals have wide-ranging repercussions for multiple illnesses, such as diabetes, cancer, seizures, and degenerative brain disease. Signals from the complexes also affect the global operation of the human brain related to sleep, appetite, circadian rhythms, and the clearing of misfolded proteins. The history of research about this molecule began when a naturally derived antibiotic was discovered in the 1970s on Easter Island in the Pacific Ocean. The antibiotic was called rapamycin, from the island’s indigenous name, Rapa Nui. Rapamycin was produced by bacteria to stop fungal reproduction, but it also had multiple other effects. It was found to increase life span in animals, similar to the way calorie restriction does. As it did in fungi, rapamycin stopped particular human cells from growing, including B lymphocytes and some cancer cells. It inhibited the actions of T cells. Later, even more functions were discovered for rapamycin. Currently, it is used to suppress the immune system after transplants. In trying to figure out how rapamycin works, researchers discovered a similar molecule that operates in somewhat the same way, but in competition with rapamycin. When a third molecule was found to be the target of both of these molecules, it was called the target of rapamycin, or TOR. Rapamycin, it appeared, turned a TOR switch on and off. Later, TOR was found in multiple species, and the version in mammals was named mTOR, for the mammalian target of rapamycin. The mTOR molecule and its large complexes were found to consist of multiple sections, each related to important cellular pathways for cell growth, inflammation, cancer inhibition, and reproduction. Complexes contain receptors triggered by hormones, immune signals, growth factors, and nutrients. They sense levels of all sorts of molecules that are needed in the cell, including amino acids, lipids, oxygen, and high-energy phosphate molecules, such as adenosine triphosphate (ATP). Signals are then sent to regulate cell pathways for each type of molecule so that enough of these necessary cellular building blocks are available for every organelle.

mTOR PROTEIN COMPLEXES
mTOR is an enzyme that catalyzes multiple chemical reactions. It removes high-energy phosphate particles from one molecule and places them on another, causing changes in activity—one part of the molecule binds to the energy particle and another to mTOR protein complexes that are part of signaling cascades. In this way, mTOR triggers messages in pathways involving the altered molecules. What is surprising is how many different signals can be sent this way to influence cycles throughout the cell at the same time. mTOR’s major focus is directing the two large multiprotein complexes that sense when there are enough nutrients for the cell to grow and divide. To regulate these global functions, mTOR stays in touch with the condition of multiple organelles. Both protein complexes are involved in multiple pathways and use various signals, often active at the same time in separate organelles with different, but interrelated, functions. With mTOR as the center, the two complexes work together to monitor information from inside and outside the cell. Together, they respond to the needs of the cell by altering basic metabolic cycles and triggering more energy and supplies when needed. There are multiple ways the two complexes provide interrelated functions. For example, when receptors on the first complex pick up information about available proteins and RNA to produce proteins, mTOR is activated and sends back signals that regulate protein manufacturing, including stimulating and inhibiting actions of ribosomes and messenger RNAs. Meanwhile, the second complex regulates the actions of the important protein actin, which forms scaffolds. With the amount of actin production directed by the first complex, signals from the second complex cause actin filaments to start constructing scaffolding in axons and dendrites, such as in response to neuroplasticity from learning. This occurs in many other cells as well but is easier to observe in neurons.

Working together, mTOR and the two complexes provide support for cell division, responses to low-oxygen conditions, and repair of damaged tissues. During cell division, activation of mTOR triggers production of key cellular ingredients, such as membranes, DNA, proteins, and organelles. 

mTOR AND LYSOSOMES
mTOR works closely with lysosomes, vesicles that remove debris and recycle material for use throughout the cell. Both mTOR and lysosomes identify levels of material needed for the cell, and they both respond with signals to increase or decrease production via recycling. mTOR complexes often sit right on the lysosome’s outer membrane for this close cooperation. Lysosomes also engage in communication with multiple organelles related to responses to infection and production of energy particles. Mitochondria have recently been observed docking with lysosomes for conversations about energy, via special communication platforms in both organelles. Collaboration between lysosomes and mTOR removes debris, including misfolded proteins, damaged organelles, and microbes. For this trashdisposal process, a series of large and small vesicles is built, with central coordination lodged in the largest lysosome vesicles, which have the ability to disassemble most types of molecules. Remarkably, lysosome vesicles are able to maintain an exact pH between 4.5 and 5 in their minuscule space, like the stomach is able to do. This highly acidic level of pH allows easier breakdown of large molecules by the lysosomes’ fifty unique enzymes. mTOR signals are vital for the three distinct mechanisms that lysosomes use to gather damaged material. One mechanism for collecting debris involves surrounding impaired molecules with vesicles, which fuse with lysosomes. Lysosomes and mTOR send signals to the Golgi to produce membranes for debris-gathering vesicles. They can also stimulate vesicles that eject debris out of a cell. A second mechanism involves lysosomes that pick up debris directly through invaginations in their membranes. A third involves proteins in the endoplasmic reticulum that place tags on debris and then send the debris to the lysosomes, where multiple transporters are produced to bring these waste molecules inside. Lysosomes and mTOR regulate each other’s activities with signals that stimulate and inhibit. When there is a problem getting the proper amount of nutrients for organelles, more recycling is triggered by mTOR signals. Signals cause increased breakdown of large molecules into constituent parts such as amino acids, nucleic acids, and simple fats and sugars. Signals also stimulate diverse lysosome sizes, which can vary as much as ten times, based on the types of materials they are working with—large proteins, nucleic acids, carbohydrates, and fats.

AMINO ACID SENSING AND PROTEIN PRODUCTION
One important function of the combined efforts of lysosomes and mTOR is responding to a lack of amino acids in protein production. A particular amino acid, leucine, was found to produce a stimulant effect on mTOR. Recently, a similar response has been found for another amino acid called glutamine. What is striking is that these two mechanisms are completely independent, occurring in entirely separate cell compartments. Yet both interact with mTOR signals to regulate cellular growth. It is not known if amino acid regulation is based on sensing just these two amino acids alone or whether other pathways haven’t been discovered yet. It is quite difficult to observe this type of signaling inside a cell. In any case, levels of these two amino acids are sensed by mTOR, and this triggers not just more recycling in lysosomes but also metabolic alterations to extract more amino acids from nutrients. As well as regulating the use of amino acids in producing proteins, mTOR directs the genetic processes related to the protein manufacturing process in at least three distinct ways. Signals from mTOR influence proteins that increase or decrease production of particular messenger RNAs from DNA. They also influence enzymes that send messenger RNA to ribosomes. Also, at the ribosome, one end of the messenger RNA molecule needs to be stimulated by mTOR to start the process. Research about regeneration after nerve injury has found more evidence about the ways mTOR stimulates the production of necessary proteins. When nerve damage occurs along the axon, signals first call for the production of mTOR molecules at the site of injury. Once multiple mTOR molecules are present, proteins needed for the repair are rapidly stimulated by these mTOR particles, using locally placed ribosomes and messenger RNAs.

ENERGY AND FOOD REGULATION
Somehow, mTOR monitors energy both at the cellular level and for the entire organism. Signaling with various organelles in the cell, mTOR picks up the amounts of energy-related nutrients available, such as lipids, then triggers their use to produce energy. At the same time, mTOR is at the center of the brain’s monitoring of energy for the entire organism. Although regulation of eating to supply energy is not well understood, it appears to utilize multiple overlapping pathways. While there are many complex brain circuits involved, two opposing circuits are primary. mTOR signals are vital to both of these—increased appetite and obesity on the one hand and decreased eating and starvation on the other. One signal for having eaten enough causes mTOR to inhibit further intake. Another set of mTOR signals is involved in the effects of restricting calories to prevent aging. 

OTHER mTOR EFFECTS ON THE BRAIN
Even more complex mTOR activity occurs in the brain. Circadian rhythms are a complex subject, since clocks have recently been found in all individual cells, in all organs, and in central brain regions. It is not yet clear how all these clocks interact with each other. But it is known that various rhythms stimulate protein production through mTOR signals. It appears that mTOR signals are involved in brain synapses related to sleep, and that learning processes during sleep also have roots in mTOR signals. Signals from mTOR complexes also affect the number of brain cells in the fetus and the creation of neural circuits. Abnormal mTOR levels in fetal growth produce brains with insufficient neurons, too many axons, distorted dendrite spines, and missing brain regions. In experiments, animals with altered mTOR show decreased learning ability and increased fearfulness. Misfolded proteins in brains can also trigger mTOR to inadvertently help cause degenerative brain disease. mTOR signals are necessary for neuroplasticity, which rapidly builds and eliminates dendrites. Both mTOR complexes work together in this process. The first mTOR complex sends messenger RNAs and ribosomes by microtubule transport to the exact locations at a synapse to produce necessary proteins. Multiple proteins that hold the synapse together either strengthen or weaken the connection between the two neurons for the neuroplasticity effect. The second complex then stimulates the actin cytoskeleton to implement these alterations in axons and dendrites using the new proteins. Faulty signaling in any of these pathways leads to degenerative brain diseases. An important aspect of brain development is directing migrating neurons and axons. mTOR signals are vital for setting up directional signals. Traveling axons search for distant destinations in the hugely complex brain architecture. Cues are provided by guidance molecules placed at particular locations along the way. Signals from mTOR stimulate local ribosomes to manufacture these proteins at the exact locations. In animal experiments, a lack of these mTOR signals and support molecules disrupts development of visual circuits.

mTOR’s WIDE-RANGING INFLUENCE
With its wide-ranging influences on cellular processes, mTOR is implicated in multiple diseases. Some of these are produced by reactive oxygen molecules that trigger mTOR to stop protein and energy production. Signals involving mTOR have been associated with an increase of abnormal misfolded proteins, such as amyloid and tau in Alzheimer’s disease and synuclein in Parkinson’s disease. Seizures have been treated by antagonizing mTOR with rapamycin. A new experimental treatment for depression with the anesthetic ketamine produces rapid results by stimulating mTOR pathways. However, rapamycin blocks the effect of this new treatment for depression. It is surprising that one molecule can be involved in so many cellular processes. This raises questions about whether particular molecules have conversations in the same way that cells and organelles do. Previous chapters show conversations among all types of human cells and their organelles and even unicellular microbes that don’t have a nucleus. Even viruses, which defy the conventional definition of life, engage in complex communication processes. We are now learning more about communication that directly comes from such molecules as mTOR, which is somehow also at the center of multiple simultaneous signaling pathways.

The mechanistic target of rapamycin (mTOR) network is an evolutionarily conserved signaling hub that senses and integrates environmental and intracellular nutrient and growth factor signals to coordinate basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation depending on the individual cell and tissue. A growing list of evidence suggests that mTOR signaling influences longevity and aging. The mechanistic (formerly mammalian) target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses


1. https://www.karger.com/Article/FullText/484629