Posts tagged genetics
Articles and news from the latest research reports.
Molecular sensor detects early signs of multiple sclerosis
For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts. But all patients share one thing in common: the disease had long been present in their nervous systems, hiding under the radar from even the most sophisticated detection methods. But now, scientists at the Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages—even before the onset of physical signs.
In a new study from the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS—and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, could spur the development of a much-needed early-detection method for this devastating disease.
MS, which afflicts millions of people worldwide, develops when the body’s immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease’s underlying causes—causes that researchers are only just beginning to understand.
Last year, Dr. Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin—a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.
"We already knew that the buildup of fibrin appears early in the development of MS—both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease." said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "In fact, we were able to detect thrombin activity even in our animal models—before they exhibited any of the disease’s neurological signs."
Air pollution and genetics combine to increase risk for autism
Exposure to air pollution appears to increase the risk for autism among people who carry a genetic disposition for the neurodevelopmental disorder, according to newly published research led by scientists at the Keck School of Medicine of the University of Southern California (USC).
"Our research shows that children with both the risk genotype and exposure to high air pollutant levels were at increased risk of autism spectrum disorder compared to those without the risk genotype and lower air pollution exposure," said the study’s first author, Heather E. Volk, Ph.D., M.P.H., assistant professor of research in preventive medicine and pediatrics at the Keck School of Medicine of USC and principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles.
The study, “Autism spectrum disorder: Interaction of air pollution with the MET receptor tyrosine kinase gene,” is scheduled to appear in the January 2014 edition of Epidemiology.
Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disability characterized by problems with social interaction, communication and repetitive behaviors. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States has an ASD.
ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.
"Although gene-environment interactions are widely believed to contribute to autism risk, this is the first demonstration of a specific interaction between a well-established genetic risk factor and an environmental factor that independently contribute to autism risk," said Daniel B. Campbell, Ph.D., assistant professor of psychiatry and the behavioral sciences at the Keck School of Medicine of USC and the study’s senior author. "The MET gene variant has been associated with autism in multiple studies, controls expression of MET protein in both the brain and the immune system, and predicts altered brain structure and function. It will be important to replicate this finding and to determine the mechanisms by which these genetic and environmental factors interact to increase the risk for autism."
Independent studies by Volk and Campbell have previously reported associations between autism and air pollution exposure and between autism and a variant in the MET gene. The current study suggests that air pollution exposure and the genetic variant interact to augment the risk of ASD.
Campbell and Volk’s team studied 408 children between 2 and 5 years of age from the Childhood Autism Risks From Genetics and the Environment Study, a population-based, case-control study of preschool children from California. Of those, 252 met the criteria for autism or autism spectrum disorder. Air pollution exposure was determined based on the past residences of the children and their mothers, local traffic-related sources, and regional air quality measures. MET genotype was determined through blood sampling.
Campbell and Volk continue to study the interaction of air pollution exposure and the MET genotype in mothers during pregnancy.
(Source: eurekalert.org)
Researchers Find Gene Responsible For Susceptibility To Panic Disorder
A study published recently in the Journal of Neuroscience points, for the first time, to the gene trkC as a factor in susceptibility to the disease. The researchers define the specific mechanism for the formation of fear memories which will help in the development of new pharmacological and cognitive treatments.
Five out of every 100 people* in Spain suffer from panic disorder, one of the diseases included within the anxiety disorders, and they experience frequent and sudden attacks of fear that may influence their everyday lives, sometimes even rendering them incapable of things like going to the shops, driving the car or holding down a job.
It was known that this disease had a neurobiological and genetic basis and for some time the search had been on to discover which genes were involved in its development, with certain genes being implicated without their physiopathological contribution being understood. Now, for the first time, researchers from the Centre for Genomic Regulation (CRG) have revealed that the gene NTRK3, responsible for encoding a protein essential for the formation of the brain, the survival of neurones and establishing connections between them, is a factor in genetic susceptibility to panic disorder.
"We have observed that deregulation of NTRK3 produces changes in brain development that lead to malfunctions in the fear-related memory system", explains Mara Dierssen, head of the Cellular and Systems Neurobiology group at the CRG. “In particular, this system is more efficient at processessing information to do with fear, the thing that makes a person overestimate the risk in a situation and therefore feel more frightened and, also, that stores that information in a more lasting and consistent manner".
Different regions of the human brain are responsible for processing this feeling, although the hippocampus and amygdala play crucial roles. On the one hand, the hippocampus is responsible for forming memories and processing contextual information, which means that the person may be afraid of being in places where they could suffer a panic attack; and on the other, the amygdala is crucial in converting this information into a physiological fear response.
Although these circuits are activated in everyone in warning situations, what the CRG researchers have discovered is that “in those people who suffer from panic disorder there is overactivation of the hippocampus and altered activation in the amygdala circuitry, resulting in exaggerated formation of fear memories”, explains Davide D’Amico, a PhD student at the CRG, co-author of the work and the article published in the Journal of Neuosciences, together with Dierssen and the researcher Mónica Santos.
They have also found that Tiagabine, a drug that modulates the brain’s fear inhibition system, is able to reverse the formation of panic memories. Although it had already been observed to alleviate certain symptoms in some patients, “we have discovered that it specifically helps restore the fear memory system”, points out Dierssen.
Panic disorder
Panic attacks are a key symptom of panic disorder. They can last several minutes, be sudden and repeated, and the sufferer has a physical reaction similar to the alarm response to real danger, involving palpitations, cold sweats, dizziness, shortness of breath, tingling in the body, nausea and stomach pain. On top of this, they feel continuously anxious when faced with the prospect of suffering another attack.
This study by the CRG researchers reveals that the way in which the memories resulting from a panic attack are stored is what ultimately ends up producing the disorder, which usually appears between 20 and 30 years of age. Although it has a genetic basis, it is also influenced by other environmental factors, such as accumulated stress. This is why the authors of the paper consider elevated environmental stress in Spanish society to have led to an increase in the occurrence of these disorders.
Currently, there is no cure for this disease, which is treated with medicines that block the more serious symptoms, as well as with cognitive therapy, which aims to help the person learn to survive the attacks better. “The problem is that drugs have many side effects and psychotherapy is not really aimed at specific moments in the process of forming and forgetting fear memories. In our work we have defined a specific creation mechanism for these fear memories that could help in the development of new drugs and, also, in identifying the key moments for applying cognitive therapy”, indicates D’Amico.
(Source: alphagalileo.org)
Breaking the Brain Clock Predisposes Nerve Cells to Neurodegeneration
As we age, our body rhythms lose time before they finally stop. Breaking the body clock by genetically disrupting a core clock gene, Bmal1, in mice has long been known to accelerate aging , causing arthritis, hair loss, cataracts, and premature death.
New research now reveals that the nerve cells of these mice with broken clocks show signs of deterioration before the externally visible signs of aging are apparent, raising the possibility of novel approaches to staving off or delaying neurodegeneration – hallmarks of Parkinson’s and Alzheimer’s diseases.
Erik Musiek, M.D., Ph.D., who was a postdoctoral fellow in the lab of Garret FitzGerald, M.D., director of the Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, took on this project four years ago. Musiek, now an assistant professor at Washington University, completed this line of research over the last two years in the lab of David Holtzman, M.D., also at WashU.
The Penn-WashU team found that the expression of certain clock genes, including Bmal1, plays a fundamental role in delaying emergence of age-related signs of decay in the brain. The clock proteins appear to do this by protecting the brain against oxidative stress – a process akin to rusting – that is normally controlled by enzymes that degrade harmful forms of oxygen generated in the course of normal metabolism. Their findings appear this week in the Journal of Clinical Investigation.
“I had lunch with Garret four years ago when I was a resident in neurology at Penn and this led me to work in his lab,” recalls Musiek. “He had studied oxidative stress in cells and the lab was actively pursuing the role of the molecular clock in cardiovascular and metabolic function. However, he hadn’t studied the brain nor the role of the clock as a regulator of oxidative stress. Others had connected the clock to signs of aging, but hadn’t focused on the brain - it seemed like an opportunity to pursue.”
They found, to their surprise, that inflammation – reflected by activation of astrocytes – brain cells involved in this type of response, among other functions — was marked in young mice in which the clock was broken by deleting Bmal1. This anticipated even more marked changes in brain pathology as the mice aged, including declines in how parts of the brain connected to each other and degenerative features in nerve-cell anatomy – all characteristic of Parkinsons and Alzheimer’s disease in humans.
“When we saw this, we knew we were on to something,” notes Musiek.
Further experiments revealed that these effects were not restricted to disrupting the function of Bmal1, but also occurred when genes – Clock and Npas2 – with which Bmal1 works in tandem, were both removed. By contrast, deletion of other genes in the clock apparatus had no such effect.
As for mechanism, the exaggerated rusting, or oxidation, was key. Expression of several antioxidant enzymes, which normally keep oxidant stress in check are themselves controlled by clock proteins, and thus were depleted when the clock was broken. Musiek and his colleagues found evidence that inflammation and the attendant oxidant stress were both increased in the brains of the mutant mice.
Experimental drugs are beginning to emerge that may retain waning rhythms driven by the molecular clock. “Erik’s studies raise the intriguing possibility of novel therapeutic approaches to delaying the progress of age-related diseases, perhaps not only those related to the brain, as suggested by the present studies, but also in other systems, such as cardiometabolic function,” says FitzGerald.
In a final twist, the Penn-WashU team pinned the neuroprotective role of the body clock to clock genes in neurons and astrocytes, rather than changes in whole-animal circadian rhythms. By selectively deleting Bmal1 in these cell types, they found that the inflammatory aspects of astrocytes, neurodegeneration, and hallmarks of oxidative stress and inflammation seen when Bmal1 was missing in all cells of the body was recapitulated.
“Our findings indicate that the protein complex of BMAL1 with CLOCK or NPAS2, in addition to, or perhaps intrinsic to the complex’s internal body-clock function, regulates protection of the brain from inflammation and oxygen free-radical induced damage. This dynamic system connects impaired clock-gene function to neurodegeneration for the first time,” says Musiek.
Different gene expression in male and female brains helps explain differences in brain disorders
UCL scientists have shown that there are widespread differences in how genes, the basic building blocks of the human body, are expressed in men and women’s brains.
Based on post-mortem adult human brain and spinal cord samples from over 100 individuals, scientists at the UCL Institute of Neurology were able to study the expression of every gene in 12 brain regions. The results are published today in Nature Communications.
They found that the way that the genes are expressed in the brains of men and women were different in all major brain regions and these differences involved 2.5% of all the genes expressed in the brain.
Among the many results, the researchers specifically looked at the gene NRXN3, which has been implicated in autism. The gene is transcribed into two major forms and the study results show that although one form is expressed similarly in both men and women, the other is produced at lower levels in women in the area of the brain called the thalamus. This observation could be important in understanding the higher incidence of autism in males.
Overall, the study suggests that there is a sex-bias in the way that genes are expressed and regulated, leading to different functionality and differences in susceptibility to brain diseases observed by neurologists and psychiatrists.
Dr. Mina Ryten, UCL Institute of Neurology and senior author of the paper, said: “There is strong evidence to show that men and women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.
“Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the brain. We have released our data so that others can assess how any gene they are interested in is expressed differently between men and women.”
(Source: ucl.ac.uk)
Scientists Pinpoint Cell Type and Brain Region Affected by Gene Mutations in Autism
A team led by UC San Francisco scientists has identified the disruption of a single type of cell – in a particular brain region and at a particular time in brain development – as a significant factor in the emergence of autism.
The finding, reported in the Nov. 21 issue of Cell, was made with techniques developed only within the last few years, and marks a turning point in autism spectrum disorders (ASDs) research.
Large-scale gene sequencing projects are revealing hundreds of autism-associated genes, and scientists have begun to leverage new methods to decipher how mutations in these disparate genes might converge to exert their effects in the developing brain.
The new research focused on just nine genes, those most strongly associated with autism in recent sequencing studies, and investigated their effects using precise maps of gene expression during human brain development.
Led by Jeremy Willsey, a graduate student in the laboratory of senior author Matthew W. State, MD, PhD, chair of the UCSF Department of Psychiatry, the group showed that this set of genes contributes to abnormalities in brain cells known as cortical projection neurons in the deepest layers of the developing prefrontal cortex during the middle period of fetal development.
Though a range of developmental scenarios in multiple brain regions are surely at work in ASDs, the ability to place these specific genetic mutations in one specific set of cells – among hundreds of cell types in the brain, and at a specific time point in human development – is a critical step in beginning to understand how autism comes about.
“Given the small subset of autism genes we studied, I had no expectation that we would see the degree of spatiotemporal convergence that we saw,” said State, an international authority on the genetics of neurodevelopmental disorders.
“This strongly suggests that though there are hundreds of autism risk genes, the number of underlying biological mechanisms will be far fewer. This is a very important clue to advance precision medicine for autism toward the development of personalized and targeted therapies.”
Complex Genetic Architecture of ASDs
ASDs, marked by deficits in social interaction and language development, as well as by repetitive behaviors and/or restricted interests, are known to have a strong genetic component.
But these disorders are exceedingly complex, with considerable variation in symptoms and severity, and there does not appear to be a small collection of mutations widely shared among all affected individuals that always lead to ASDs.
Instead, with the rise of new sequencing methods over the past several years, researchers have identified many rare, non-inherited, spontaneous mutations that appear to act in combination with other genetic and non-genetic factors to cause ASDs. According to some estimates, mutations in as many as 1,000 genes could play a role in the development of these disorders.
While researchers have been heartened that specific genes are now rapidly being tied to ASDs, State said the complex genetic architecture of ASDs is also proving to be challenging.
“If there are 1,000 genes in the population that can contribute to risk in varying degrees and each has multiple developmental functions, it is not immediately obvious how to move forward to determine what is specifically related to autism. And without this, it is very difficult to think about how to develop new and better medications,” he said.
Focusing on Nine Genes
To begin to grapple with those questions, the researchers involved in the new study first selected as “seeds” the nine genes that have been most strongly tied to ASDs in recent sequencing research from their labs and others.
Importantly, these nine genes were chosen solely because of the statistical evidence for a relationship to ASDs, not because their function was known to fit a theory of the cause of ASDs. “We asked where the leads take us, without any preconceived idea about where they should take us,” said State.
The team then took advantage of BrainSpan, a digital atlas assembled by a large research consortium, including co-author Nenad Šestan, MD, PhD, and colleagues at Yale School of Medicine. Based on donated brain specimens, BrainSpan documents how and where genes are expressed in the human brain over the lifespan.
The scientists, who also included Bernie Devlin, PhD, of The University of Pittsburgh School of Medicine; Kathryn Roeder, PhD, of Carnegie-Mellon University; and James Noonan, PhD, of Yale School of Medicine, used this tool to investigate when and where the nine seed genes join up with other genes in “co-expression networks” to wire up the brain or maintain its function.
The resulting co-expression networks were then tested using a variety of pre-determined criteria to see if they showed additional evidence of being related to ASDs. Once this link was established, the authors were then able to home in on where in the brain and when in development these networks were localizing, which proved to be in cortical projection neurons found in layers 5 and 6 of the prefrontal cortex, and during a time period spanning 10 to 24 weeks after conception. Notably, a study using different methods and published in the same issue of Cell also implicates cortical projection neurons in ASDs.
“To see these gene networks as highly connected as they are, as convergent as they are, is quite amazing,” said Willsey “An important outcome of this study is that for the first time it gives us the ability to design targeted experiments based on a strong idea about when and where in the brain we should be looking at specific genes with specific mutations.”
In addition to its importance in ASD research, State sees the new work as a reflection of the tremendous value of “big science” efforts, such as large-scale collaborative genomic studies and the creation of foundational resources such as the BrainSpan atlas.
“We couldn’t have done this even two years ago,” State said, “because we didn’t have the key ingredients: a set of unbiased autism genes that we have confidence in, and a map of the landscape of the developing human brain. This work combines large-scale ‘-omics’ data sets to pivot into a deeper understanding of the relationship between complex genetics and biology.”
Study reveals how variant forms of APOE protein impact risk of Alzheimer’s disease
Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.
"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”
The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood.
Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.
Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain.
In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain.
"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”
(Source: massgeneral.org)
Gene linked to common intellectual disability
University of Adelaide researchers have taken a step forward in unravelling the causes of a commonly inherited intellectual disability, finding that a genetic mutation leads to a reduction in certain proteins in the brain.
ARX is among the top four types of intellectual disability linked to the X-chromosome in males. So far, 115 families, including many large Australian families, have been discovered to carry an ARX (Aristaless related homeobox) mutation that gives rise to intellectual disability.
"There is considerable variation in the disability across families, and within families with a single mutation. Symptoms among males always include intellectual disability, as well as a range of movement disorders of the hand, and in some cases severe seizures," says Associate Professor Cheryl Shoubridge, Head of Molecular Neurogenetics with the University of Adelaide’s Robinson Institute.
ARX mutations were first discovered by the University of Adelaide’s Professor Jozef Gecz in 2002. To date, researchers have detected 52 different ARX mutations and 10 distinct clinical syndromes.
Associate Professor Shoubridge is lead author of a new paper on ARX intellectual disability published in the journal Human Molecular Genetics.
In laboratory studies, Associate Professor Shoubridge’s team has shown that mutations lead to a significant reduction in ARX proteins in the brain, but the actual causes and mechanisms involved in this remain unknown. Her team tested six genes that the ARX protein interacts with, and found that one of them - a gene likely to be important to early brain development - appears to be adversely affected by the reduction of ARX proteins.
"This plays an important role in setting up architecture and networks in the brain, which become disrupted due to the mutation", Associate Professor Shoubridge says.
"The discovery of this genetic link is an important step forward but there is still much work to be done. We’re now looking further at the mechanism of the reduction in ARX protein and what that means for the brain at a functional level."
Associate Professor Shoubridge says up to 3% of the population is affected by some kind of intellectual disability, costing $14.7 billion each year in Australia alone.
"The personal cost to families is enormous, especially in the most severe cases. Being able to unravel why and how these disabilities occur is very important to us and to the many people whose lives are affected by these conditions," she says.
(Source: adelaide.edu.au)
New Therapeutic Target Identified for ALS and Frontotemporal Degeneration
A team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontotemporal degeneration, the second most frequent dementia.
Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.
The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.
In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.
A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.
“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.
The researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.
“This led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein. This selective silencing of a toxic RNA is the holy grail of gene silencing approaches, and we showed we had accomplished it,” Lagier-Tourenne added.
Targeting the sense strand RNAs with a specific ASO did not, however, affect the antisense strand foci nor did it correct the signature of gene expression changes. “Doing that will require separate targeting of the antisense strand – or both - and has now become a critical question,“ Lagier-Tourenne said.
“This approach is exciting as it links two neurodegenerative diseases, ALS and FTD, to the field of expansion, which has gained broadened interest from investigators,” said co-principal investigator John Ravits, MD, UC San Diego Department of Neurosciences. “At the same time, our study also demonstrates the – to now – unrecognized role of anti-sense RNA and its potential as a therapeutic target.”
(Source: health.ucsd.edu)
Oxytocin gene partly responsible for how adolescents feel in company
Loneliness: could there be a genetic explanation for it? Yes, to some extent! At least in the case of young female adolescents who, it appears, are more likely to feel lonely in everyday life if they have a specific variant of the gene that regulates how oxytocin – also known as the ‘bonding hormone’ – is received in the brain. Boys who carry this variant are not lonelier but, like girls, respond more strongly to a negative social environment. These findings were published this week in the academic journal PlosONE.
Oxytocin is a hormone with an important role in social behaviour. In the period following birth, it is an important factor in the bonding process between mother and baby, but it also has an influence on other relationships. The gene that regulates oxytocin-sensitivity in the brain varies between one person and another. Some people are less sensitive to oxytocin and therefore more likely to feel lonely. Various indicators have already suggested this. This prompted a group of behavioural researchers in Nijmegen to carry out a fresh and in-depth study of oxytocin effects in a group in which ‘belonging’ is of paramount importance: young adolescents.
A large group, frequently surveyed
The study involved 278 adolescents, 58 per cent of whom were girls. They were contacted via their smartphones nine times a day over a six-day period and asked to report how they felt and who they were with. The presence of the variant of the oxytocin receptor gene OXTR was also determined. ‘This is a new approach to researching the interaction between gene variation and the environment,’ explains Eeske van Roekel, the lead author of the article published online in PlosONE on Monday 4 November. ‘By asking the subjects nine times a day “How do you feel? Who are you with? What do you think of the people you are with?,” we managed to put together a clear picture of how adolescents feel in everyday life. These real-time reports are more reliable than responses after the event.’
Lonelier with specific OXTR variant
‘Our most important finding was that girls who carried a certain variant of the oxytocin gene in their DNA felt lonelier than girls who did not. Boys with this variant were also adversely affected by negative company at the weekend: their feelings increased the longer they were in such company, while boys without this variant were unaffected. These findings apply to both boys and girls.’ The measured effects are small but still relevant, says Van Roekel. ‘These methods reveal more about actual everyday experiences than methods that ask people once at a later date to describe how they felt.’ Heightened sensitivity to negative company in the case of this specific variant was only visible at weekends. How can that be explained? ‘We surmise that it’s because you have more freedom in the weekend to choose the people you mix with than through the week,’ says Van Roekel. ‘Then it makes a deeper impression if they treat you in a negative manner.’
New trend
No-one knows yet exactly how the receptor gene works. ‘We still don’t know how it translates into, for example, oxytocin levels in the brain,’ says Van Roekel. ‘So more research is needed on that front.’ Research on connections between genes and behaviour is developing gradually. ‘We think that our approach, which takes multiple measurements in the daily life of adolescents, has a lot to offer when it comes to discovering connections.’ Van Roekel conducted her research in the group of Professor Rutger Engels at the Behavioural Science Institute of Radboud University Nijmegen.