Autism  

A new study suggests that in children with autism, something in the process goes awry, leaving an oversupply of synapses in at least some parts of the brain. The study is an important step forward in understanding what’s happening in the brains of people with autism.

A utism was recently speculated to be a possible sign of the next stage of human evolution by Juan Enriquez.  Now, children and adolescents with autism have been found to have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development.  The study ws conducted by neuroscientists at Columbia University Medical Center (CUMC).

The reseach was published in the online issue of the journal Neuron.

Synapses are the points where neurons connect and communicate with each other, so the researchers speculate the excessive synapses may have profound effects on how the brain functions.

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.

"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."

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.

Neurons in brains from people with autism do 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. Image Source: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

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.

Neurons in brains from people with autism do 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. (Image credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center)

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.

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. Image: Guomei Tang/CUMC.

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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.”




SOURCE  Columbia University Medical Center

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 Life Extension  

Researchers, using a combination of genetic changes have multiplied the longevity of the nematode worm C.elegans by a factor that, in humans, would mean a 400 to 500-year old lifespan.

New research in simple animals suggests that combining mutants can lead to radical lifespan extension. Scientists at the Buck Institute combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans. The research, done at the Buck Institute and published online in Cell Reports, introduces the possibility of combination therapy for aging and the maladies associated with it.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Lead scientist and Buck faculty Pankaj Kapahi, PhD, said single mutations in TOR (in this case RSKS-1) usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms – added together they would be expected to extend longevity by 130 percent. “Instead, what we have here is a synergistic five-fold increase in lifespan,” Kapahi said. “The two mutations set off a positive feedback loop in specific tissues that amplified lifespan. Basically these worms lived to the human equivalent of 400 to 500 years.”

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Kapahi said the research points to the possibility of using combination therapies for aging, similar to what is done for cancer and HIV. “In the early years, cancer researchers focused on mutations in single genes, but then it became apparent that different mutations in a class of genes were driving the disease process,” he said. “The same thing is likely happening in aging.” Kapahi said this research could help explain why scientists are having a difficult time identifying single genes responsible for the long lives experienced by human centenarians. “It’s quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives.”

Former Buck postdoctoral fellow Di Chen, PhD, now an associate professor at the Model Animal Research Center, Nanjing University, China, lead author of the study, said that the positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. “The germline was the key tissue for the synergistic gain in longevity – we think it may be where the interactions between the two mutations are integrated,” Chen said. “The finding has implications for similar synergy between the two pathways in more complex organisms.”

Kapahi said ideally the research would move into mice as a way of determining if the lifespan-extending synergy extends into mammals. “The idea would be to use mice genetically engineered to have suppressed insulin signaling, and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway.”


SOURCE  Buck Institute for Research on Aging

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 Anti-Aging  

Mice suffering from age-related heart disease saw a significant improvement in cardiac function after treatment with the FDA-approved drug rapamycin for just three months. Research at the Buck Institute shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that can extend lifespan in mice as much as 14 percent.

Elderly mice suffering from age-related heart disease saw a significant improvement in cardiac function after being treated with the FDA-approved drug rapamycin for just three months.

 The research, led by a team of scientists at the Buck Institute for Research on Aging, shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that has been shown to extend the lifespan of mice as much as 14 percent. There are implications for human health in the research appearing online in Aging Cell: heart disease is the leading cause of death in the U.S., claiming nearly 600,000 lives per year.

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Rapamycin is an immunosuppressant drug which can be used to help prevent organ rejection after transplantation. It is also included in treatment regimens for some cancers. In this study, rapamycin was added to the diets of mice that were 24 months old – the human equivalent of 70 to 75 years of age. Similar to humans, the aged mice exhibited enlarged hearts, a general thickening of the heart wall and a reduced efficiency in the hearts ability to pump blood.

The mice were examined with ultrasound echocardiography before and after the three-month treatment period - using metrics closely paralleling those used in humans. Buck Institute faculty Simon Melov, PhD, the senior author of the study, said age-related cardiac dysfunction was either slowed or reversed in the treated mice. “When we measured the efficiency of how the heart pumps blood, the treated mice showed a remarkable improvement from where they started. In contrast, the untreated mice saw a general decline in pumping efficiency at the end of the same three month period,” he said.

“This study provides the first evidence that age-related heart dysfunction can be improved even in late life via appropriate drug treatment,” added Melov, who said the treated mice saw a reduction in heart size, reduced stress signaling in heart tissues and a reduction in inflammation.

Buck researchers, utilizing genome analysis tools, uncovered suites of related genes which rapamycin modulates in the heart. “Rapamycin affected the expression of genes involved in calcium regulation, mitochondrial metabolism, hypertrophy and inflammation,” said Melov. “We also carried out behavioral assessments which showed the treated mice spent more time on running wheels than the mice who aged without intervention.”

“Little has been known about the functional ramifications of rapamycin in mammalian tissues,” said Buck Institute President and CEO Brian Kennedy, PhD, a co-author of the paper. “These findings are significant because we have no interest in simply extending lifespan without an accompanying improvement in the health and quality of life.” He added, “It is particularly encouraging that, in this case, an already-approved drug that extends lifespan also improved function late in life.”

Chronic treatment with rapamycin has been problematic in both humans and mice; the drug has the potential to cause deleterious metabolic side effects including weight gain and glucose insensitivity. Melov said in this study, the drug had only mild transient metabolic effects. Future studies will focus on better understanding the molecular targets that drive age-related heart dysfunction, and why rapamycin treatment is so beneficial to the aging hearts.

Researchers at the Mayo clinic are now recruiting seniors with cardiac artery disease for a clinical trial involving the drug.

SOURCE  The Buck Institute for Research on Aging

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 Cancer Research  

University of Montreal researchers have discovered a novel molecular mechanism that can potentially slow the progression of some cancers and other diseases of abnormal growth. In the May 23 edition of the prestigious journal Cell, scientists from the University of Montreal explain how they found that the anti-cancer and anti-proliferative drug rapamycin slows down or prevents cells from dividing.

University of Montreal researchers have discovered a novel molecular mechanism that can potentially slow the progression of some cancers and other diseases of abnormal growth. In a recent edition of the prestigious journal Cell, scientists from the University of Montreal explained how they found that the anti-cancer and anti-proliferative drug rapamycin slows down or prevents cells from dividing.

Rapamycin has also been found to have anti-aging properties which may be linked to the resarchers' discovery.

“Cells normally monitor the availability of nutrients and will slow down or accelerate their growth and division accordingly. A key monitor of nutrients is a protein called the Target of Rapamycin (TOR), but we do not know the details of how this protein feeds signals downstream to control growth” says Dr. Stephen Michnick, senior author and a University of Montreal biochemistry professor.

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He adds that, “we were surprised to find that TOR hooks up to a circuit that controls the exit of cells from division which in turn modulates the RNA message that codes for a key cell cycle regulator called B-cyclin”.

In collaboration with Daniel Zenklusen, also a University of Montreal biochemistry professor and lead author and doctoral candidate Vincent Messier, they discovered that when cells are starved for nutrients TOR sends a signal to shut down production of a chemical message in the form of RNA to synthesize B cyclin ”, Dr. Michnick explained.

“We also found that TOR acts through a previously unforeseen intermediary, a protein that makes small chemical modifications to proteins normally stabilizing B cyclin RNA ”, he added. “We have known that starvation and a drug that mimics starvation, rapamycin, affects B cyclin synthesis, but we didn't know how. Our studies now point to one mechanism”, noted Dr. Messier.

Dr. Zenklusen emphasized that, "this is an important finding with implications for our understanding on how the normal organism interprets its environment to control growth and it was a surprise to find a mechanism that works through the RNA that codes for a regulatory protein”. Dr. Michnick adds, “rapamycin is a promising therapy for some cancers and other devastating maladies such as the rare lung disease called lymphangioleiomyomatosis (LAM). It remains to be seen whether the pathway we have discovered might be an alternative target for the development of therapeutics against these diseases.”


SOURCE  University of Montreal

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