Neuroscience

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Bipolar Disorder Discovery at the Nano Level

A nano-sized discovery by Northwestern Medicine® scientists helps explain how bipolar disorder affects the brain and could one day lead to new drug therapies to treat the mental illness. 

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Scientists used a new super-resolution imaging method — the same method recognized with the 2014 Nobel Prize in chemistry — to peer deep into brain tissue from mice with bipolar-like behaviors. In the synapses (where communication between brain cells occurs), they discovered tiny “nanodomain” structures with concentrated levels of ANK3 — the gene most strongly associated with bipolar disorder risk. ANK3 is coding for the protein ankyrin-G. 

“We knew that ankyrin-G played an important role in bipolar disease, but we didn’t know how,” said Northwestern Medicine scientist Peter Penzes, corresponding author of the paper. “Through this imaging method we found the gene formed in nanodomain structures in the synapses, and we determined that these structures control or regulate the behavior of synapses.” 

Penzes is a professor in physiology and psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. The results were published Oct. 22 in the journal Neuron. 

High-profile cases, including actress Catherine Zeta-Jones and politician Jesse Jackson, Jr., have brought attention to bipolar disorder. The illness causes unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks. About 3 percent of Americans experience bipolar disorder symptoms, and there is no cure. 

Recent large-scale human genetic studies have shown that genes can contribute to disease risk along with stress and other environmental factors. However, how these risk genes affect the brain is not known. 

This is the first time any psychiatric risk gene has been analyzed at such a detailed level of resolution. As explained in the paper, Penzes used the Nikon Structured Illumination Super-resolution Microscope to study a mouse model of bipolar disorder. The microscope realizes resolution of up to 115 nanometers. To put that size in perspective, a nanometer is one-tenth of a micron, and there are 25,400 microns in one inch. Very few of these microscopes exist worldwide.

“There is important information about genes and diseases that can only been seen at this level of resolution,” Penzes said. “We provide a neurobiological explanation of the function of the leading risk gene, and this might provide insight into the abnormalities in bipolar disorder.”

The biological framework presented in this paper could be used in human studies of bipolar disorder in the future, with the goal of developing therapeutic approaches to target these genes.

(Source: northwestern.edu)

Filed under bipolar disorder ANK3 synapses ankyrin-G mental illness genetics neuroscience science

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Scientists Link ALS Progression to Increased Protein Instability A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. “Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff. Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates. “The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Getzoff. Striking in the Prime of Life ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association’s Ice Bucket Challenge has enhanced public awareness of the disease. ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms. SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary “sporadic” ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don’t agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease. One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations. In 2003, based on their and others’ studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the “framework destabilization” hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up—and that accumulating SOD aggregation somehow triggers disease. Faster Clumping, Worse Disease In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS “hotspot” affect SOD protein stability. To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, “wild-type” SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab’s SIBYLS beamline. “We could detect differences between the two proteins even before we accelerated the aggregation process,” said David S. Shin, a research scientist in Tainer’s laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley. The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS. Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS. What could explain these SOD mutants’ diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions—and this ability was lower for the SOD mutants associated with more severe ALS. “There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions,” said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab. Toward New Therapies In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions—and thus are more likely to misfold and stick together in aggregates. Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons. “Because mutant SODs get bent out of shape more easily,” said Getzoff, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.” The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants. “If our hypothesis is correct,” said Shin, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”

Scientists Link ALS Progression to Increased Protein Instability

A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

“Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff.

Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates.

“The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Getzoff.

Striking in the Prime of Life

ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association’s Ice Bucket Challenge has enhanced public awareness of the disease.

ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms.

SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary “sporadic” ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don’t agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease.

One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations.

In 2003, based on their and others’ studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the “framework destabilization” hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up—and that accumulating SOD aggregation somehow triggers disease.

Faster Clumping, Worse Disease

In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS “hotspot” affect SOD protein stability.

To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, “wild-type” SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab’s SIBYLS beamline.

“We could detect differences between the two proteins even before we accelerated the aggregation process,” said David S. Shin, a research scientist in Tainer’s laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley.

The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS.

Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS.

What could explain these SOD mutants’ diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions—and this ability was lower for the SOD mutants associated with more severe ALS.

“There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions,” said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab.

Toward New Therapies

In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions—and thus are more likely to misfold and stick together in aggregates.

Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons.

“Because mutant SODs get bent out of shape more easily,” said Getzoff, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.”

The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants.

“If our hypothesis is correct,” said Shin, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”

Filed under ALS Lou Gehrig’s disease superoxide dismutase SOD SOD1 genetics neuroscience science

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Greater Rates of Mitochondrial Mutations Discovered in Children Born to Older Mothers The discovery of a “maternal age effect” by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells — and the transmission of these mutations to children — could provide valuable insights for genetic counseling. These mutations cause more than 200 diseases and contribute to others such as diabetes, cancer, Parkinson’s disease, and Alzheimer’s disease. The study found greater rates of the mitochondrial DNA variants in children born to older mothers, as well as in the mothers themselves. The research will be published in the early online edition of the Proceedings of the National Academy of Sciences on October 13, 2014. Mitochondria are structures within cells that produce energy and that contain their own DNA. “Many mitochondrial diseases affect more than one system in the human body,” said Kateryna Makova, professor of biology and one of the study’s primary investigators. “They affect organs that require a lot of energy, including the heart, skeletal muscle, and brain. They are devastating diseases and there is no cure, so our findings about their transmission are very important.” The multidisciplinary research team set out to learn whether maternal age is important in the accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in the child as a result of transmission. Collaborating with Ian Paul, a pediatrician at the Penn State Milton S. Hershey Medical Center, they took samples of blood and of cells inside the cheek from 39 healthy mother-child pairs. Because mtDNA is inherited only maternally, paternal mtDNA was not a factor in the study. Studying healthy individuals gave the researchers a baseline for future studies of disease-causing mutations. Through DNA sequencing, they found more mutations in blood and cheek cells in the older mothers in the study. Maternal age of study participants ranged from 25 to 59. “This finding is not surprising,” Makova said, “because as we age, cells keep dividing, and therefore we will have more mutant genes.” But finding greater rates of mutations in children born to the older mothers did come as a surprise. The researchers believe a similar mutation process is occurring both in the cells of the mothers’ bodies and in their germ lines. The study led to another important discovery about egg-cell development. Although it was known that developing egg cells go through a “bottleneck” period that decreases the number of mtDNA molecules, scientists didn’t know how small or large this bottleneck is. “If the bottleneck is large, the genetic makeup of the mother’s mitochondria will be passed to her children,” Makova explained. “However, if it is tiny — if there is a severe decrease in mitochondrial molecules during the egg-cell development — then the genetic makeup of the child might differ dramatically from that of the mother. What we discovered is that this bottleneck is indeed very small.” This finding is especially important for mothers who have a mitochondrial disease. For many mitochondrial diseases, 70 to 80 percent of molecules need to have the disease-causing variant for the disease to manifest itself. But for others, only 10 percent of the mtDNA molecules with the variant are needed to cause disease. “If the bottleneck is very small, as we’ve found in our study, these percentages can change dramatically,” Makova said. “Knowing the size of the bottleneck allows us to predict, within a range, the percentage of disease-carrying molecules that will be passed on to the child.” Knowledge about both the maternal age effect and the bottleneck size is useful in family planning. “We have some predictive power now and can assist genetic counselors in advising couples about the chances of mitochondrial diseases being passed to the next generation,” Makova said. “Everyone is concerned about Down syndrome because that is a common genetic problem. We have now added another set of genetic disorders that also might be affected by the age of the mother. It is good for couples to have this knowledge as they make family-planning decisions.”

Greater Rates of Mitochondrial Mutations Discovered in Children Born to Older Mothers

The discovery of a “maternal age effect” by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells — and the transmission of these mutations to children — could provide valuable insights for genetic counseling. These mutations cause more than 200 diseases and contribute to others such as diabetes, cancer, Parkinson’s disease, and Alzheimer’s disease. The study found greater rates of the mitochondrial DNA variants in children born to older mothers, as well as in the mothers themselves. The research will be published in the early online edition of the Proceedings of the National Academy of Sciences on October 13, 2014.

Mitochondria are structures within cells that produce energy and that contain their own DNA. “Many mitochondrial diseases affect more than one system in the human body,” said Kateryna Makova, professor of biology and one of the study’s primary investigators. “They affect organs that require a lot of energy, including the heart, skeletal muscle, and brain. They are devastating diseases and there is no cure, so our findings about their transmission are very important.”

The multidisciplinary research team set out to learn whether maternal age is important in the accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in the child as a result of transmission. Collaborating with Ian Paul, a pediatrician at the Penn State Milton S. Hershey Medical Center, they took samples of blood and of cells inside the cheek from 39 healthy mother-child pairs. Because mtDNA is inherited only maternally, paternal mtDNA was not a factor in the study. Studying healthy individuals gave the researchers a baseline for future studies of disease-causing mutations.

Through DNA sequencing, they found more mutations in blood and cheek cells in the older mothers in the study. Maternal age of study participants ranged from 25 to 59. “This finding is not surprising,” Makova said, “because as we age, cells keep dividing, and therefore we will have more mutant genes.” But finding greater rates of mutations in children born to the older mothers did come as a surprise. The researchers believe a similar mutation process is occurring both in the cells of the mothers’ bodies and in their germ lines.

The study led to another important discovery about egg-cell development. Although it was known that developing egg cells go through a “bottleneck” period that decreases the number of mtDNA molecules, scientists didn’t know how small or large this bottleneck is. “If the bottleneck is large, the genetic makeup of the mother’s mitochondria will be passed to her children,” Makova explained. “However, if it is tiny — if there is a severe decrease in mitochondrial molecules during the egg-cell development — then the genetic makeup of the child might differ dramatically from that of the mother. What we discovered is that this bottleneck is indeed very small.”

This finding is especially important for mothers who have a mitochondrial disease. For many mitochondrial diseases, 70 to 80 percent of molecules need to have the disease-causing variant for the disease to manifest itself. But for others, only 10 percent of the mtDNA molecules with the variant are needed to cause disease. “If the bottleneck is very small, as we’ve found in our study, these percentages can change dramatically,” Makova said. “Knowing the size of the bottleneck allows us to predict, within a range, the percentage of disease-carrying molecules that will be passed on to the child.”

Knowledge about both the maternal age effect and the bottleneck size is useful in family planning. “We have some predictive power now and can assist genetic counselors in advising couples about the chances of mitochondrial diseases being passed to the next generation,” Makova said. “Everyone is concerned about Down syndrome because that is a common genetic problem. We have now added another set of genetic disorders that also might be affected by the age of the mother. It is good for couples to have this knowledge as they make family-planning decisions.”

Filed under mitochondria mitochondrial mutations maternal age mtDNA genetics neuroscience science

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Mining big data yields Alzheimer’s discovery

Scientists at The University of Manchester have used a new way of working to identify a new gene linked to neurodegenerative diseases such as Alzheimer’s. The discovery fills in another piece of the jigsaw when it comes to identifying people most at risk of developing the condition.

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Researcher David Ashbrook and colleagues from the UK and USA used two of the world’s largest collections of scientific data to compare the genes in mice and humans. Using brain scans from the ENIGMA Consortium and genetic information from The Mouse Brain Library, he was able to identify a novel gene, MGST3 that regulates the size of the hippocampus in both mouse and human, which is linked to a group of neurodegenerative diseases. The study has just been published in the journal BMC Genomics.

David, who works in Dr Reinmar Hager’s lab at the Faculty of Life Sciences, says: “There is already the ‘reserve hypothesis’ that a person with a bigger hippocampus will have more of it to lose before the symptoms of Alzheimer’s are spotted. By using ENIGMA to look at hippocampus size in humans and the corresponding genes and then matching those with genes in mice from the BXD system held in the Mouse Brain Library database we could identify this specific gene that influences neurological diseases.”

He continues: “Ultimately this could provide another biomarker in the toolkit for identifying those at greatest risk of developing diseases such as Alzheimer’s.”

Dr Hager, senior author of the study, says: “What is critical about this research is that we have not only been able to identify this specific gene but also the networks it uses to influence a disease like Alzheimer’s. We believe this information will be incredibly useful for future studies looking at treatments and preventative measures.”

The ENIGMA Consortium is led by Professor Paul Thompson based at the University of California, Los Angeles, and contains brain images and gene information from nearly 25,000 subjects. The Mouse Brain Library, established by Professor Robert Williams based at the University of Tennessee Health Science Center, contains data on over 10,000 brains and numerical data from just over 20,000 mice. 

David explains why combining the information held by both databases is so useful: “The key advantage of working this way is that it is much easier to identify a genetic variant in mice as they live in such controlled environments. By taking the information from mice and comparing it to human gene information we can identify the same variant much more quickly.”

And David thinks this way of working will be used more often in the future: “We are living in a big data world thanks to the likes of the Human Genome Project and post-genome technologies. A lot of that information is now widely shared so by mining what we already know we can learn so much more, advancing our knowledge of diseases and ultimately improving detection and treatment.”

(Source: manchester.ac.uk)

Filed under alzheimer's disease MGST3 hippocampus brain structure genomics genetics neuroscience science

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Why is educational achievement heritable?

New research, led by King’s College London finds that the high heritability of exam grades reflects many genetically influenced traits such as personality, behaviour problems, and self-efficacy and not just intelligence.

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The study, published today in the Proceedings of the National Academy of Sciences (PNAS), looked at 13,306 twins at age 16 who were part of the Medical Research Council (MRC) funded UK Twins Early Development Study (TEDS). The twins were assessed on a range of cognitive and non-cognitive measures, and the researchers had access to their GCSE (General Certificate of Secondary Education) scores.

In total, 83 scales were condensed into nine domains: intelligence, self-efficacy (confidence in one’s own academic ability), personality, well-being, home environment, school environment, health, parent-reported behaviour problems and child reported behaviour problems.

Identical twins share 100% of their genes, and non-identical twins (just as any other siblings) share 50% of the genes that vary between people. Twin pairs share the same environment (family, schools, teachers etc). By comparing identical and non-identical twins, the researchers were able to estimate the relative contributions of genetic and environmental factors. So, if overall, identical twins are more similar on a particular trait than non-identical twins, the differences between the two groups are due to genetics, rather than environment.

Eva Krapohl, joint first author of the study, from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s, says: “Previous work has already established that educational achievement is heritable. In this study, we wanted to find out why that is. What our study shows is that the heritability of educational achievement is much more than just intelligence – it is the combination of many traits which are all heritable to different extents.

“It is important to point out that heritability does not mean that anything is set in stone. It simply means that children differ in how easy and enjoyable they find learning and that much of these differences are influenced by genetics.”

The researchers found that the heritability of GCSE scores was 62%.  Individual traits were between 35% and 58% heritable, with intelligence being the most highly heritable. Together, the nine domains accounted for 75% of the heritability of GCSE scores.

Heritability is a population statistic which does not provide any information at an individual level. It describes the extent to which differences between children can be ascribed to DNA differences, on average, in a particular population at a particular time. 

(Source: kcl.ac.uk)

Filed under heritability educational achievement intelligence genetics neuroscience science

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Schizophrenia not a single disease but multiple genetically distinct disorders

New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.

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The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry.

About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.

“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.”

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness.

In some patients with hallucinations or delusions, for example, the researchers matched distinct genetic features to patients’ symptoms, demonstrating that specific genetic variations interacted to create a 95 percent certainty of schizophrenia. In another group, they found that disorganized speech and behavior were specifically associated with a set of DNA variations that carried a 100 percent risk of schizophrenia.

“What we’ve done here, after a decade of frustration in the field of psychiatric genetics, is identify the way genes interact with each other, how the ‘orchestra’ is either harmonious and leads to health, or disorganized in ways that lead to distinct classes of schizophrenia,” Cloninger said. 

Although individual genes have only weak and inconsistent associations with schizophrenia, groups of interacting gene clusters create an extremely high and consistent risk of illness, on the order of 70 to 100 percent. That makes it almost impossible for people with those genetic variations to avoid the condition. In all, the researchers identified 42 clusters of genetic variations that dramatically increased the risk of schizophrenia.

“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained Dragan Svrakic, PhD, MD, a co-investigator and a professor of psychiatry at Washington University. “When one study would identify an association, no one else could replicate it. What was missing was the idea that these genes don’t act independently. They work in concert to disrupt the brain’s structure and function, and that results in the illness.”

Svrakic said it was only when the research team was able to organize the genetic variations and the patients’ symptoms into groups that they could see that particular clusters of DNA variations acted together to cause specific types of symptoms.

Then they divided patients according to the type and severity of their symptoms, such as different types of hallucinations or delusions, and other symptoms, such as lack of initiative, problems organizing thoughts or a lack of connection between emotions and thoughts. The results indicated that those symptom profiles describe eight qualitatively distinct disorders based on underlying genetic conditions.

The investigators also replicated their findings in two additional DNA databases of people with schizophrenia, an indicator that identifying the gene variations that are working together is a valid avenue to explore for improving diagnosis and treatment.

By identifying groups of genetic variations and matching them to symptoms in individual patients, it soon may be possible to target treatments to specific pathways that cause problems, according to co-investigator Igor Zwir, PhD, research associate in psychiatry at Washington University and associate professor in the Department of Computer Science and Artificial Intelligence at the University of Granada, Spain.

And Cloninger added it may be possible to use the same approach to better understand how genes work together to cause other common but complex disorders.

“People have been looking at genes to get a better handle on heart disease, hypertension and diabetes, and it’s been a real disappointment,” he said. “Most of the variability in the severity of disease has not been explained, but we were able to find that different sets of genetic variations were leading to distinct clinical syndromes. So I think this really could change the way people approach understanding the causes of complex diseases.”

(Source: news.wustl.edu)

Filed under schizophrenia mental illness genes genetic variations genetics genomics neuroscience science

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8,000-Year-Old Mutation Key to Human Life at High Altitudes

In an environment where others struggle to survive, Tibetans thrive in the thin air on the Tibetan Plateau, with an average elevation of 14,800 feet. A University of Utah led discovery that hinged as much on strides in cultural diplomacy as on scientific advancements, is the first to identify a genetic variation, or mutation, that contributes to the adaptation, and to reveal how it works. The research appears online in the journal Nature Genetics on Aug. 17, 2014.

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“These findings help us understand the unique aspects of Tibetan adaptation to high altitudes, and to better understand human evolution,” said Josef Prchal, M.D., senior author and University of Utah professor of internal medicine.

For his research, Prchal needed Tibetans to donate blood, from which he could extract their DNA, a task that turned out to be more difficult than he ever imagined. It took several trips to Asia, meeting with Chinese officials and representatives of exiled Tibetans in India, to get the necessary permissions to recruit subjects for the study. But he quickly learned that official documents would not be enough. Wary of foreigners, the Tibetans refused to participate.

To earn the Tibetans’ trust, Prchal obtained a letter of support from the Tibetan spiritual leader, the Dalai Lama. “The Dalai Lama felt that a better understanding of the adaptation would be helpful not only to the Tibetan community but also to humanity at large,” said Prchal. He also enlisted the help of native Tibetan Tsewang Tashi, M.D., an author and clinical fellow at the Huntsman Cancer Institute at the University of Utah. More than 90 Tibetans, both from the U.S. and abroad, volunteered for the study.

Published in Science in 2010, Prchal’s group was the first to establish that there was a genetic basis to Tibetan high altitude adaptation. In the intervening years, first author Felipe Lorenzo, M.D., Ph.D., pioneered new techniques to tease out the secret to one of the adaptations from a “GC-rich” region of the Tibetans’ DNA that was particularly difficult to penetrate.

Their efforts were worth it; the DNA had a fascinating story to tell. About 8,000 years ago, the gene EGLN1 changed by a single DNA base pair. Today, a relatively short time later on the scale of human history, the vast majority of Tibetans – 88 percent - have the genetic variation, and it is virtually absent from closely related lowland Asians. The findings indicate the tiny genetic change endows its carriers with a selective advantage.

Prchal collaborated with experts throughout the world, including co-senior author Peppi Koivunen, Ph.D., from Biocenter Oulu in Finland, to determine that the newly identified genetic variation protects Tibetans by decreasing an aversive over-response to low oxygen. In those without the adaptation, the thin air causes their blood to become thick with oxygen-carrying red blood cells, often causing long-term complications such as heart failure. The EGLN1 variation, together with other unidentified genetic changes, collectively support life at high altitudes.

Prchal says the research also has broader implications. Because oxygen plays a central role in human physiology and disease, a deep understanding of how high altitude adaptations work may lead to novel treatments for various conditions, including cancer. “There is much more that needs to be done, and this is just the beginning,” he said.

When traveling with Tashi in Asia, Prchal was surprised at how he was able to get Tibetans to grasp the research they were being asked to take part in. Tashi simply helped them realize that their ability to adapt to life at high altitude was unique. “They usually responded by a little initial surprise quickly followed by agreement,” said Tashi. “It was as if I made them realize something new, which only then became obvious.”

Listen to an interview with Josef Prchal, Tsewang Tashi, and Felipe Lorenzo on The Scope Radio.

Filed under genetic mutation EGLN1 high altitude adaptation evolution genetics hypoxia neuroscience science

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Our genes determine the traces that stress leaves behind on our brains

Our individual genetic make-up determines the effect that stress has on our emotional centres. These are the findings of a group of researchers from the MedUni Vienna. Not every individual reacts in the same way to life events that produce the same degree of stress. Some grow as a result of the crisis, whereas others break down and fall ill, for example with depression. The outcome is determined by a complex interaction between depression gene versions and environmental factors.

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The Vienna research group, together with international cooperation partners, have demonstrated that there are interactions between stressful life events and certain risk gene variants that subsequently change the volume of the hippocampus forever.

The hippocampus is a switching station in the processing of emotions and acts like a central interface when dealing with stress. It is known to react very sensitively to stress. In situations of stress that are interpreted as a physical danger (‘distress’), it shrinks in size, which is a phenomenon observed commonly in patients with depression and one which is responsible for some of their clinical symptoms. By contrast, positive stress (‘eustress’), of the kind that can occur in emotionally exciting social situations can actually cause the hippocampus to increase in size.

According to the results of the study, just how stressful life events impact on the size of the hippocampus depends on more than just environmental factors. There are genes that determine whether the same life event causes an increase or decrease in the volume of the hippocampus, and which therefore defines whether the stress is good or bad for our brain. The more risk genes an individual has, the more negative an impact the “life events” have on the size of the hippocampus. Where there are no or only a few risk genes, this life event can actually have a positive effect.

Examining life crises
As part of the study, carried out at the University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team obtained quantitative information from healthy test subjects about stressful life events, such as deaths in the family, divorce, unemployment, financial losses, relocations, serious illnesses or accidents.

A high-resolution anatomical magnetic resonance scan was also carried out (at the High-Field MR Centre of Excellence, Department of MR Physics, led by Ewald Moser). The University Department of Laboratory Medicine (Harald Esterbauer and colleagues) carried out the gene analyses (COMT Val158Met, BDNF Val66Met, 5-HTTLPR). At the University Department of Psychiatry and Psychotherapy, primary author Ulrich Rabl measured the volume of the test subjects’ hippocampi using computer-assisted techniques and analysed the results in the context of the genetic and environmental data.
"People with the three gene versions believed to encourage depression had a smaller hippocampus than those with fewer or none of these gene versions, even though they had the same number of stressful life events," says study leader Lukas Pezawas, describing the results. People with only one or even none of the risk genes, on the other hand, had an enlarged hippocampus with similar life events.

The study highlights the importance of gene and environment interaction as a determining factor for the volume of the hippocampus. “These results are important for understanding neurobiological processes in stress-associated illnesses such as depression or post-traumatic stress disorder. It is ultimately our genes that determine whether stress makes us psychologically unwell or whether it encourages our mental health,” explains Pezawas.

The study, published in the highly respected “Journal of Neuroscience”, was funded by a special research project of the FWF (Austrian Science Fund) (SFB-35, led by Harald Sitte) and presented as a highlight at the international conference on “Organization for Human Brain Mapping”.

(Source: meduniwien.ac.at)

Filed under stress hippocampus genes environment genetics neuroscience science

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Neurons at work Film editors play a critical role by helping shape raw footage into a narrative. Part of the challenge is that their work can have a profound impact on the finished product — with just a few cuts in the wrong places, comedy can become tragedy, or vice versa. A similar process, “alternative splicing,” is at work inside the bodies of billions of creatures — including humans. Just as a film editor can change the story with a few cuts, alternative splicing allows cells to stitch genetic information into different formations, enabling a single gene to produce up to thousands of different proteins. Harvard scientists say they’ve now been able to observe that process within the nervous system of a living creature. Read more

Neurons at work

Film editors play a critical role by helping shape raw footage into a narrative. Part of the challenge is that their work can have a profound impact on the finished product — with just a few cuts in the wrong places, comedy can become tragedy, or vice versa.

A similar process, “alternative splicing,” is at work inside the bodies of billions of creatures — including humans. Just as a film editor can change the story with a few cuts, alternative splicing allows cells to stitch genetic information into different formations, enabling a single gene to produce up to thousands of different proteins.

Harvard scientists say they’ve now been able to observe that process within the nervous system of a living creature.

Read more

Filed under C. elegans motor neurons mRNA splicing genetics neuroscience science

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Blood-oxytocin levels in normal range in children with autism

Autism does not appear to be solely caused by a deficiency of oxytocin, but the hormone’s universal ability to boost social function may prove useful in treating a subset of children with the developmental disorder, according to new findings from the Stanford University School of Medicine and Lucile Packard Children’s Hospital Stanford.

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Low levels of oxytocin, a hormone involved in social functioning, have for years been suspected of causing autism. Prior research seeking a link has produced mixed results. Now, in the largest-ever study to test the purported connection, the range of blood oxytocin levels has been shown to be the same in children with autism as that observed in two comparison groups: children with autistic siblings and children without autistic siblings. In other words, similar numbers of children with low, medium and high oxytocin levels were found in all three groups.

A paper describing the new findings was published online Aug. 4 in Proceedings of the National Academy of Sciences.

Although autism was not directly linked to oxytocin deficiency, the Stanford team found that higher oxytocin levels were linked to better social functioning in all groups. All children with autism have social deficits, but in the study these deficits were worst in those with the lowest blood oxytocin and mildest in those with the highest oxytocin. In the comparison groups, children’s social skills also fell across a range that correlated to their oxytocin levels.

Regulator of social functioning

“Oxytocin appears to be a universal regulator of social functioning in humans,” said Karen Parker, PhD, assistant professor of psychiatry and behavioral sciences and the lead author of the study. “That encompasses both typically developing children as well as those with the severe social deficits we see in children with autism.”

Autism is a developmental disorder that affects 1 of every 68 children in the United States. It is characterized by social and communication deficits, repetitive behaviors and sensory problems. The new study included 79 children with autism, 52 of their unaffected siblings and 62 unrelated children without autism. All of the children were between the ages of 3 and 12.

“It didn’t matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated,” said Antonio Hardan, MD, professor of psychiatry and behavioral sciences and the study’s senior author. Hardan is a child and adolescent psychiatrist who treats children with autism at the hospital.

“The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic,” he said. “It’s much more complex: Oxytocin is a vulnerability factor that has to be accounted for, but it’s not the only thing leading to the development of autism.”

The researchers caution, however, that blood oxytocin measurements may be different than oxytocin levels in the cerebrospinal fluid bathing the brain, which they did not measure.

In addition to examining blood oxytocin levels, the researchers examined the importance of small variations in the gene coding for the oxytocin receptor. Certain receptor variants were correlated to higher scores on standard tests of social ability, the study found.

Inheriting social abilities

The team also discovered that blood levels of oxytocin are highly heritable: The levels are influenced by inheritance to about the same degree as adult height, which is often described as being strongly influenced by genetics.

"What our study hints at is that social function may be heritable in families," Parker said.

The study will help to guide future research to determine whether oxytocin is a useful autism treatment. The study’s findings suggest that some children with autism — such as the subset of kids with autism who have naturally low oxytocin levels, or those with oxytocin receptor gene variants associated with worse social functioning — might benefit most from oxytocin-like drugs.

 “Autism is so heterogeneous,” Parker said. “If we can identify biomarkers that help us identify the patients most likely to benefit from a specific therapy, we expect that will be very useful.”

(Source: med.stanford.edu)

Filed under autism oxytocin social interaction social function genetics neuroscience science

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