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 (see post on Shape Is Function in the Neuron).
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.
When 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 processes 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
The 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 the 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 and 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
How 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?