(Image caption: In a study of brains from children with autism, neurons in brains from autistic patients did not undergo normal pruning during childhood and adolescence. The images show representative neurons from unaffected brains (left) and brains from autistic patients (right); the spines on the neurons indicate the location of synapses. Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center)

Children with Autism Have Extra Synapses in Brain

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC). Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions. The study was published in the August 21 online issue of the journal Neuron.

A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviors have appeared.

“This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism,” said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of New York State Psychiatric Institute, who was not involved in the study.

Although the drug, rapamycin, has side effects that may preclude its use in people with autism, “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said the study’s senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.

During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviors; pruning eliminates about half of these cortical synapses by late adolescence. Synapses are known to be affected by many genes linked to autism, and some researchers have hypothesized that people with autism may have more synapses.

To test this hypothesis, co-author Guomei Tang, PhD, assistant professor of neurology at CUMC, examined brains from children with autism who had died from other causes. Thirteen brains came from children ages two to 9, and thirteen brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison.

Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.

By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.

“It’s the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” Dr. Sulzer said, “although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviors.”

Clues to what caused the pruning defect were also found in the patients’ brains; the autistic children’s brain cells were filled with old and damaged parts and were very deficient in a degradation pathway known as “autophagy.” Cells use autophagy (a term from the Greek for self-eating) to degrade their own components.

Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses, “Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”

The researchers could restore normal autophagy and synaptic pruning—and reverse autistic-like behaviors in the mice—by administering rapamycin, a drug that inhibits mTOR. The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.

Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.

“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”

Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what’s happening in the brains of people with autism.

“The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute. That’s a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments,” he said.

“The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease.”

Children with autism have extra synapses in brain: May be possible to prune synapses with drug after diagnosis

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC). Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions. The study was published in the August 21 online issue of the journal Neuron.

Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, David Sulzer. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron, 2014; DOI: 10.1016/j.neuron.2014.07.040

In a study of brains from children with autism, researchers found that autistic brains did not undergo normal pruning during childhood and adolescence. The images show representative neurons from autistic (left) and control (right) brains; the spines on the neurons indicate the location of synapses.  Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

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Children with Autism Have Extra Synapses in Brain

Read the full article Children with Autism Have Extra Synapses in Brain at NeuroscienceNews.com.

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC). Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions.

The research is in Neuron. (full access paywall)

Research: “Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits” by Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, and David Sulzer in Neuron. doi:10.1016/j.neuron.2014.07.040

Image: 1) A neuron from the brain of young person with autism. A new study finds that young people with autism have excess synapses. Credit Guomei Tang and Mark S. Sonders/CUMC.

2) Autistic brains do not undergo normal pruning during childhood and adolescence. The images show representative neurons from autistic (left) and control (right) brains; the spines on the neurons indicate the location of synapses. Credit Guomei Tang and Mark S. Sonders/CUMC.

3) A “self-eating” impairment in the neurons of autism patients is shown with the decrease of an autophagy marker (red color) compared to unaffected neurons. Credit Guomei Tang/CUMC.

Children with autism have extra brain synapses

Children with autism have extra synapses in their brain due to a slowdown in the normal brain “pruning” process during development, say US neuroscientists.

In the autistic brains, synaptic density was more than 50 per cent higher than that in the brains of children without autism and sometimes two-thirds greater.

The researchers traced the pruning effect to a protein called mTOR. When mTOR is overactive brain cells lose much of their self-trimming ability.

To restore normal synaptic pruning and reverse autistic-like behaviours in mice, the researchers administered rapamycin, an immunosuppressant drug that prevents organ rejection and inhibits mTOR.

However, even if the findings are confirmed — and Sulzer notes that treatments that work in lab animals often fail in people — it is unlikely that rapamycin would be used in people with autism because its widescale immune-suppressing effects would likely cause serious side effects.

"But there could be better drugs," says Sulzer "such as a molecule that dials up production of synapse-pruning proteins."

One remaining puzzle is how the mice’s brains, or the drug, know which synapses to keep and which to prune.

"But the mice started behaving normally" after receiving the synapse-pruning drug, "which suggests the right ones are being pruned," says Sulzer.

Read more

An axial or horizontal magnetic resonance image of a glioblastoma multiforme brain tumor in a human patient. Image courtesy of RadioGraphics.

Killing killer brain tumors

Glioblastoma multiforme are the most common and lethal of brain tumors in adults. The median survival time after diagnosis is just 12 to 14 months. The condition is almost invariably fatal.

Compounding their deadliness, GBMs tend to become quickly resistant to current drug treatments. In a paper published this week in the Proceedings of the National Academy of Sciences, researchers at the Ludwig Institute for Cancer Research at the University of California, San Diego say they may know why, describing a new molecular pathway that might eventually lead to more effective GBM therapies.

The study, headed Paul Mischel, MD, a professor in the department of pathology in UC San Diego’s School of Medicine, looked at a signaling pathway called the mammalian target of rapamycin or mTOR and at a multipurpose gene-encoded protein called promyleocytic leukemia or PML.

The work builds upon earlier research suggesting that the best way to kill GBM tumors is to block the signaling pathways that preserve and promote their survival.

MTOR is “hyperactivated” in close to 90 percent of glioblastomas and plays a critical role in regulating tumor growth and survival. It is considered to be a major therapeutic target. However, PML causes resistance to drugs designed to inhibit mTOR signaling. When glioblastoma patients are treated with mTOR-inhibitory drugs, PML levels rise and drug resistance grows, eventually rendering the drugs useless.

So the researchers went looking for something that suppresses or reduces PML levels, which would leave tumors more vulnerable to mTOR inhibitor drugs. They believe they’ve found it in arsenic trioxide, a molecule whose therapeutic use dates back to traditional Chinese medicine. In low doses, arsenic trioxide has been found to degrade the PML protein in leukemia patients. In their tests, the UC San Diego scientists discovered that it did the same in mice with brain tumors, reversing resistance to mTOR inhibitory drugs so that there was massive cancer cell death and significant tumor shrinkage, with no ill side effects.

Mischel and colleagues are now planning to test the therapy in people. You can read more about their research here.

Game changing neuroimaging study proves children with autism have extra synapses in brain. Thoughts health innovators? http://bit.ly/1wgA6uz

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in normal brain ‘pruning’ process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC).

SickPapes Special on Suren N. Sehgal (1932-2003) and the discovery of the TOR pathway

From:

Vézina, C., Kudelski, A., Sehgal, S.N., 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726.

To:

Laplante, M., Sabatini, D.M., 2012. mTOR signaling in growth control and disease. Cell 149, 274–293. 

In our younger and more vulnerable years, it was exciting to learn “how things work.” But, as we’ve grown older, and gotten more seriously into smoking weed, it is the discovery stories behind ”how things work” - the ways that people figured it out in the first place - that we find truly spine-tingling. We’ve said it before, and we’ll say it again: there is nothing better than choosing a hot-ass research topic, strapping yourself in, and doing a psychadelic literature search all the way back to the beginning to see how it all got started. The euphoria from the resulting “PubMed High” is, truly, nature’s candy.

Case in point: TOR signaling. TOR signaling is a highly conserved pathway that cells use to respond to nutrients and other external signals, and is therefore a central focus for tons of important biomedical research on conditions that involve cell growth and/or nutrition, things like cancer, diabetes, and obesity. There are, quite literally, shit-loads of papes about TOR - trust me, I’ve smoked them all. 

Given how “mainstream” and “biomedical” this field is, I was not at all emotionally prepared to learn how the pathway was discovered. To begin, look no further than the name of the pathway: TOR, which stands for “Target of rapamycin.” This name refers to the fact that the pathway responds to (i.e. is disrupted by) a drug called “rapamycin.” Rapamycin, it turns out, is where the story gets freaky-deaky, and leads us to the trippiest place on earth, Easter Island. And Easter Island, as we know, is where all scientific discoveries ultimately begin. 

In 1964, a team of Canadian microbiologists went to Easter Island, looking for soil microbes that produce natural antibiotics. One of the soil samples they collected contained a bacterial strain which secreted a factor with potent anti-fungal activity. Dr. Suren N. Sehgal and his team named this factor rapamycin, in honor of the local name for Easter Island, Rapa Nui.  

There is a cliche of scientific discovery stories that goes like this: an unsuspecting biologist, studying some relatively obscure organism, winds up identifying a molecule that has wildly important and far-ranging applications. Penicillin is the most famous example, but similar stories are told about Green Fluorescent Protein (from jellyfish; now used to visualize proteins in vivo), thermostable Taq polymerase (from a hot-springs bacteria; now used to amplify DNA), and CRISPR-associated enzymes (from yogurt bacteria, now used to achieve GATTACA-esque dystopic fantasies about modifying babies).

Of course, by now it has also become almost cliche to point out that this Surprise-turn-NobelPrize narrative is total bullshit, and all of these discoveries were in fact made by excellent, forward-thinking scientists who knew what they were doing. Not to say that there wasn’t some element of serendipity in how revolutionary such discoveries ultimately became, but it’s important to emphasize that these discoveries were not lucky one-offs. As many mythbusters have pointed out, even the “accidental” discovery of Penicillin was actually done by a guy who had devoted his whole career to identifying anti-bacterial compounds, and involved lots of work by others who are rarely credited. As it has been written before: “Tenacity frequently precedes rather than follows serendipity.” 

Point is: Dr. Sehgal did not just “get lucky.” While it might be tempting to imagine him as an esoteric microbiologist with no idea how important rapamycin would become, this was not how it went down at all. Dr. Sehgal ran a lab at a pharmaceutical company that was set up specifically to systematically screen for anti-microbial factors produced by other microbes. Once they identified these Easter Island bacteria, they quickly isolated the active compound (rapamycin), figured out how to produce it in quantity, and then discovered that, in addition to it’s anti-fungal properties, rapamycin worked in mammals as a powerful immunosuppressant. (Rapamycin was eventually turned into a drug to help suppress the immune system after organ transplants.) Rapamycin was soon discovered to also suppress the proliferation of some kinds of tumors. 

In the 50 years since the discovery of rapamycin, an enormous number of researchers have worked to identify the pathway that is targeted by rapamycin (the TOR pathway), and have begun to figure out the complex ways that this this pathway links external signals (like nutrition) to control of the cell cycle and other basic metabolic processes. This explains how rapamycin suppresses tumor growth (by blocking the progression of the cell cycle), and it suppresses the immune system (by blocking the proliferation of immune cells in response to antigens). That’s what we call a “hot pathway.” 

To read more about Suren N. Sehgal, check out this moving tribute to his research and life, which celebrates “his life and his contributions to mankind.”  

Watch on vascularbiology.tumblr.com
Regulation of growth by the mTOR pathway

Regulation of growth by the mTOR pathway

Air date: Wednesday, March 20, 2013, 3:00:00 PM

Wednesday Afternoon Lecture Series 

The mammalian target of rapamycin (mTOR), the target of the immunosuppressive drug rapamycin, is the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. This pathway becomes deregulated in many human cancers and plays an important role in the control of metabolism and aging. Sabatini’s lab has identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival through Akt. These complexes, mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. New results on the regulation and functions of the mTORC1 and mTORC2 pathways will be discussed. 

Author: David M. Sabatini, M.D., Ph.D., MIT 

Runtime: 00:59:04 

Mammalian Target of Rapamycin Inhibitor in Systemic Lupus Erythematosus

T cell dysfunction in lupus is also influenced by abnormal mitochondrial oxidative metabolism. Lymphocytes from SLE patientsl showed higher production of reactive oxygen intermediates, lower ATP content, and increased rates of necrosis. Mitochondrial transmembrane potential is controlled by the mammalian target of rapamycin (mTOR). Treatment of SLE patients with rapamycin, an mTOR inhibitor (also known as sirolimus), led to normalization of CD3-zeta expression and calcium flux in T cells. Lupus-prone mice treated with sirolimus showed reduced proteinuria, nephritis, and anti-dsDNA antibodies. In preliminary report, seven of nine SLE patients refractory to conventional immunosuppresion showed an improvement in disease activity scores after treatment with sirolimus. Phase II trials of sirolimus in SLE and lupus nephritis are in progress.

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Skeletal muscle myoblasts! I think middle one looks like a dancing man. We can use antibodies to essentially make proteins light up in different colors. Here, I am making mTOR light up in red and a protein which marks the lysosome (a subcellular organelle responsible for digesting materials within the cell) light up in green to determine if mTOR is found on the lysosome. 

Degradation of Tiam1 by Casein Kinase 1 and the SCFβTrCP Ubiquitin Ligase Controls the Duration of mTOR-S6K signaling.

Degradation of Tiam1 by Casein Kinase 1 and the SCFβTrCP Ubiquitin Ligase Controls the Duration of mTOR-S6K signaling.

J Biol Chem. 2014 Aug 14;

Authors: Magliozzi R, Kim J, Low TY, Heck AJ, Guardavaccaro D

Abstract
T-cell lymphoma invasion and metastasis 1 (Tiam1) is a guanine nucleotide exchange factor that specifically controls the activity of the small GTPase Rac, a key regulator of cell adhesion, proliferation and survival. Here, we report that in response to mitogens, Tiam1 is degraded by the ubiquitin-proteasome system via the SCFbetaTrCP ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiam1 to the F-box protein betaTrCP via its degron sequence and subsequent Tiam1 ubiquitylation and proteasomal degradation. The proteolysis of Tiam1 is prevented by betaTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. Expression of a stable Tiam1 mutant that is unable to interact with betaTrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCFbetaTrCP-mediated degradation of Tiam1 controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.

PMID: 25124033 [PubMed - as supplied by publisher]



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Aberrant mTOR signaling impairs whole body physiology

Aberrant mTOR signaling impairs whole body physiology

(University of Basel) The protein mTOR is a central controller of growth and metabolism. Deregulation of mTOR signaling increases the risk of developing metabolic diseases such as diabetes, obesity and cancer. In the current issue of the journal Proceedings of the National Academy of Sciences, researchers from the Biozentrum of the University of Basel describe how aberrant mTOR signaling in the…

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Aberrant mtor signaling impairs whole body physiology

The protein mTOR is a central controller of growth and metabolism. Deregulation of mTOR signaling increases the risk of developing metabolic diseases such as diabetes, obesity and cancer. Researchers now describe how aberrant mTOR signaling in the liver not only affects hepatic metabolism but also whole body physiology.



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