Jon Lieff, M.D.
Past President, American Association for Geriatric Psychiatry
Assistant Clinical Professor, Tufts University Medical School
There are several competing theories of what mind could be in nature. Is it an emergent property of molecules and neurons in the brain, an electromagnetic energy field interacting with molecules, cells, organisms and brains or something else? There is no definite answer. The unusual intelligent behavior of cells including bacteria, intestinal epithelial cells, skin cells, platelets, T cells, astrocytes and microglia is now acknowledged. This complex behavior of cells, without a brain, raises the question of whether mind exists throughout nature and somehow interacts with molecules and cells. The question asked in each of these articles is how can a cell behave as if it has a brain?
Surprisingly this same decision-making, communication and complex behavior is also observed in viruses. A question then arises whether jumping genes and prions demonstrate similar types of complex behavior as viruses. This would imply that even a molecule could exhibit a form of intelligence.
This article describes the remarkable behavior of the small molecule mTOR that forms many large complexes along with other molecules. By sensing many different cellular processes at once and simultaneously responding to all of them, this one molecule appears to behave as if it had a brain.
The information in this article is distilled from a variety of more complex research reviews. It is a simplified description of behavior outlined in extreme detail in molecular biological research articles. Two excellent recent reviews of this material are The Neurology of mTOR, Jonathan O. Lipton and Mustafa Sahin,
Neuron 84, October 22, 2014 a2014 Elsevier Inc. and Nutrient-sensing Mechanisms and Pathways, Alejo Efeyan, William C. Comb, doi:10.1038/nature14190. Other references appear at the end of the article.
Many Functions of mTOR
How can one complex protein function as if it is a nervous system? mTOR is able to monitor a large amount of different external and internal information and use this data to make critical decisions and take many actions. The decisions involve multiple pathways controlling cellular growth and the amount of protein manufacturing. Corresponding actions include triggering specific genetic networks for many different tasks including balancing of basic metabolism and energy production. It is difficult to imagine how mTOR can perform so many different critical functions that integrate so much information related to the cell or an organisms relation to its environment.
Because its 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. In addition, even while behaving like a brain itself, mTOR has critical functions throughout the human brain.
Major accomplishments of mTOR are directly regulating the amount of proteins created , the amount of RNA made from DNA (transcription), critical elements of 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 making 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 the discovery of the antibiotic rapamycin in a microbe on Easter Island, known locally as Rapa Nui. Rapamycin was found to block a protein, which was called “mammalian target of rapamycin” or mTOR. Rapamycin stops 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, many more functions were discovered.
mTOR is the critical mediator of many different pathways and signals including 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 and together. They are often found in different cellular compartments, but act 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 many large proteins that form the structure of the complexes 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 messenger RNA 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. The mechanisms for other amino acids are not known. Since it is very difficult to study metabolic pathways, the many ways that mTOR senses nutrients is only now being discovered. For, examples, mTOR is stimulated by insulin, growth factors, blood factors, phosphatidic acids and oxidative processes.
mTOR Complex 2 (mTORC2) is itself composed of 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. Their functions are based on complex shape as with other large proteins.
A variety of powerful neurotrophic factors stimulate mTOR pathways including glutamate, special guidance molecules, 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, when more or less is needed at different times and places. mTOR triggers or suppresses 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 involved in regulating the use of lipids for energy in the cell. These factors sense lipid nutrients, regulate axonal myelin and produce neuronal action potentials. 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 an oxidative state to glycolytic pathways. This same mechanism is also involved in stimulating the growth of more blood vessels when low oxygen is caused by a stroke or other damage causing low blood flow to tissues.
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 Control of Autophagy
Autophagy is a complex process that cells use 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.
Autophagy in the brain is complex and important, but not well understood. 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 correlated with 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 do not produce enough neurons. In fact, mTOR appears to be critical in creating the windows of brain development seen in babies. But, this effect when exaggerated in research goes both ways—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 of these factors 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 is also part of 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 wherein 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 the brain
- Immune systems interact with mTOR in creating neuronal circuits, such as insulin regulating synapses using MHC immune molecules
- During brain injury or spinal cord injury, mTOR uses(((“uses fetal mechanisms that have been quiescent from the fetal period until the injury 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 potassium channels in dendrites.
- Activities of mTOR stimulate creation of the specific brain neuronal circuits.
mTOR In Neuroplasticity Learning and Memory
It was first learned that rapamycin stopped the strengthening of synapses for neuroplasticity by stopping production of critical proteins. Later, it was found that as is the case for 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 general learning and memory 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 are also 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 ones are centered 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 channeled through mTOR to produce special molecules to initiate or to stop eating. mTOR also appears to be critical to the anti aging effects of calorie restriction.
mTOR is further critically involved in circadian rhythms that triggers gene networks and specific protein production that regulates it. However, 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, such as 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 mTOR pathway decreasing manufacture of proteins by stopping ribosomes. Altering mTORC1 stops mitochondria respiration and production of energy.
- In tuberous sclerosis and other tumors, abnormal pathways produce abnormal neurons and large glia.
- mTOR abnormalities produce symptoms autism among many other symptoms.
- Genetic mTOR tumor diseases cause seizures, which respond to treatment with rapamycin, possibly related to effects on migration of neurons and axons, production of axons and dendrites and regulation of action potentials.
- Factors that trigger mTOR pathways such as lack of oxygen, inflammation and the electrical events in neurons can interact with genetic defects in the complex pathways.
Because mTOR is the most important measure of nutrients and energy needs, it can, also, be related to aging. Although, the mechanism is not known in animals, rapamycin increases life span. It is also involved in the mechanism by which calorie restriction increases life span, probably through the control of protein manufacturing.
- mTOR signaling is associated with both increased amyloid and abnormal tau 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.
- In Parkinson’s, rapamycin increased autophagy and decreased abnormal alpha-synuclein proteins.
- Both autophagy and mTOR are related to increases in Huntington’s abnormal protein clumps.
- 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.
How Can a Molecule Behave As If It is a Brain?
How can one molecule be a sensor for many different nutrients, oxygen, energy, and then control protein synthesis and help remodel the brain? Previous posts have noted that cells, such as microbes, behave as if they have a brain by integrating many senses and making many different decisions simultaneously. Others have demonstrated unusual behavior of viruses with only a handful of genes and proteins, but are still able to perform hundreds of complex behaviors, while tricking vastly larger human immune cells. Observing the actions and capabilities of viruses, jumping genes and prions, the question has to be raised about 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?
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