1. Study explains why stress hormone can prevent disorders after exposure to traumatic event

    September 25, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    People who have suffered from traffic accidents, war combat, terrorist attacks and exposure to other traumatic events have an increased likelihood of developing diseases. These diseases can be psychological and physical, such as heart problems and cancer. The current preventive treatments based on psychological support and drugs are effective in some cases. Unfortunately, these treatments do not work for many individuals. It is also known that the earlier the treatment starts the better to prevent future negative consequences.

    Researchers at the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc-UAB, Spain) have discovered in a study with mice and humans that the Ppm1f (Protein phosphatase 1f) gene expression is one of the most highly regulated after exposure to traumatic stress. Moreover, Ppm1f is associated with posttraumatic stress disorder (PTSD), depression and anxiety. The main function of Ppm1f is to regulate the activity of the protein Camk2 (Calmodulin-dependent protein kinase 2), which is key in many processes of the human body such as memory, the heart’s functioning and the immune system.

    According to Dr. Raül Andero Galí, lead researcher in this study, “Once we discovered the relationship between the Ppm1f gene and different psychological disorders after exposure to traumatic stress, we wanted to find an effective drug to prevent these changes and its negative consequences on the brain.” Dr Andero is scientist at the INc-UAB. It was already known that dosing the stress hormone — a glucocorticoid — few hours after exposure to a traumatic event may decrease the likelihood of developing psychological disorders. Thus, the scientists administered the hormone to mice one hour after exposure to stress. “The results confirmed a decrease in the symptoms of anxiety and depression, and also that this effect is because the Ppm1f gene changes are prevented,” explains Dr. Eric Velasco, researcher at the INc-UAB and co-author of the study.

    “The apparent contradiction that the stress hormone decreases the likelihood of developing diseases after exposure to traumatic stress is one of the greatest paradoxes of current medicine” Andero says. “This study sheds light on this paradox and uncovers a way by which the stress hormone could prevent diseases, at least psychologically, through regulation of the Ppm1f gene” he adds.

    Until now, the stress hormone has been administered to people in very few cases. “Our discovery opens the door to a broader application and to the development of treatments aimed specifically at regulating this gene’s functions,” says Antonio Florido, researcher of the INc-UAB and also co-author of the paper.

    The study was carried out in collaboration with the universities of Harvard and Emory (United States). This work is published in Biological Psychiatry, one of the most important journals in Neuroscience. The UAB researchers are currently interested in collaborating with other laboratories and obtaining funding to continue the studies of Ppm1f associated with other disorders such as cardiovascular diseases and cancer in order to verify whether their results are comparable in other diseases and potentially prevent them.


  2. Study suggests another gene that may significantly influence development of dementia and Alzheimer’s

    September 21, 2017 by Ashley

    From the University of Southern California press release:

    The notorious genetic marker of Alzheimer’s disease and other forms of dementia, ApoE4, may not be a lone wolf.

    Researchers from USC and the University of Manchester have found that another gene, TOMM40, complicates the picture. Although ApoE4 plays a greater role in some types of aging-related memory ability, TOMM40 may pose an even greater risk for other types.

    TOMM40 and APOE genes are neighbors, adjacent to each other on chromosome 19, and they are sometimes used as proxies for one another in genetic studies. At times, scientific research has focused chiefly on one APOE variant, ApoE4, as the No. 1 suspect behind Alzheimer’s and dementia-related memory decline. The literature also considers the more common variant of APOE, ApoE3, neutral in risk for Alzheimer’s disease.

    USC researchers believe their new findings raise a significant research question: Has TOMM40 been misunderstood as a sidekick to ApoE4 when it is really a mastermind, particularly when ApoE3 is present?

    “Typically, ApoE4 has been considered the strongest known genetic risk factor for cognitive decline, memory decline, Alzheimer’s disease or dementia-related onset,” said T. Em Arpawong, the study’s lead author and a post-doctoral fellow in the USC Dornsife College of Letters, Arts and Sciences Department of Psychology. “Although prior studies have found some variants of this other gene TOMM40 may heighten the risk for Alzheimer’s disease, our study found that a TOMM40 variant was actually more influential than ApoE4 on the decline in immediate memory – the ability to hold onto new information.”

    Studies have shown that the influence of genes associated with memory and cognitive decline intensifies with age. That is why the scientists chose to examine immediate and delayed verbal test results over time in conjunction with genetic markers.

    “An example of immediate recall is someone tells you a series of directions to get somewhere and you’re able to repeat them back,” explained Carol A. Prescott, the paper’s senior author who is a professor of psychology at USC Dornsife College and professor of gerontology at the USC Davis School of Gerontology. “Delayed recall is being able to remember those directions a few minutes later, as you’re on your way.”

    The study was published in the journal PLOS ONE on Aug. 11.

    Prescott and Arpawong are among the more than 70 researchers at USC who are dedicated to the prevention, treatment and potential cure of Alzheimer’s disease. The memory-erasing illness is one of the greatest health challenges of the century, affecting 1 in 3 seniors and costing $236 billion a year in health care services. USC researchers across a range of disciplines are examining the health, societal and political effects and implications of the disease.

    In the past decade, the National Institute on Aging has nearly doubled its investment in USC research. The investments include an Alzheimer Disease Research Center.

    Tracking memory loss

    For the study, the team of researchers from USC and The University of Manchester utilized data from two surveys: the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing. Both data sets are nationally representative samples and include results of verbal memory testing and genetic testing.

    The research team used verbal test results from the U.S. Health and Retirement Survey, collected from 1996 to 2012, which interviewed participants via phone every two years. The researchers utilized the verbal memory test scores of 20,650 participants, aged 50 and older who were tested repeatedly to study how their memory changed over time.

    To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10.

    The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer’s or some other form of dementia.

    “There is usually a drop-off in scores between the immediate and the delayed recall tests,” Prescott said. “In evaluating memory decline, it is important to look at both types of memory and the difference between them. You would be more worried about a person who has scores of 10 and 5 than a person with scores of 6 and 4.”

    The first person is worrisome because five minutes after reciting the 10 words perfectly, he or she can recall only half of them, Prescott said. The other person wasn’t perfect on the immediate recall test, but five minutes later, was able to remember a greater proportion of words.

    To prevent bias in the study’s results, the researchers excluded participants who reported that they had received a likely diagnosis of dementia or a dementia-like condition, such as Alzheimer’s. They also focused on participants identified as primarily European in heritage to minimize population bias. Results were adjusted for age and sex.

    The researchers compared the U.S. data to the results of an independent replication sample of participants, age 50 and up, in the English Longitudinal Study of Aging from 2002 to 2012. Interviews and tests were conducted every two years.

    Genetic markers of dementia

    To investigate whether genes associated with immediate and delayed recall abilities, researchers utilized genetic data from 7,486 participants in the U.S. Health and Retirement Study and 6,898 participants in the English Longitudinal Study of Ageing.

    The researchers examined the association between the immediate and delayed recall results with 1.2 million gene variations across the human genome. Only one, TOMM40, had a strong link to declines in immediate recall and level of delayed recall. ApoE4 also was linked but not as strongly.

    “Our findings indicate that TOMM40 plays a larger role, specifically, in the decline of verbal learning after age 60,” the scientists wrote. “Further, our analyses showed that there are unique effects of TOMM40 beyond ApoE4 effects on both the level of delayed recall prior to age 60 and decline in immediate recall after 60.”

    Unlike ApoE4, the ApoE3 variant is generally thought to have no influence on Alzheimer’s disease or memory decline. However, the team of scientists found that adults who had ApoE3 and a risk variant of TOMM40, were more likely to have lower memory scores. The finding suggests that TOMM40 affects memory – even when ApoE4 is not a factor.

    The team suggested that scientists should further examine the association between ApoE3 and TOMM40 variants and their combined influence on decline in different types of learning and memory.

    “Other studies may not have detected the effects of TOMM40,” Prescott said. “The results from this study provide more evidence that the causes of memory decline are even more complicated than we thought before, and they raise the question of how many findings in other studies have been attributed to ApoE4 that may be due to TOMM40 or a combination of TOMM40 and ApoE4.”


  3. Using DNA to predict schizophrenia, autism

    September 15, 2017 by Ashley

    From the Osaka University press release:

    Osaka University researchers show in a multi-institute collaboration that a single amino acid substitution in the protein CX3CR1 may act as predictor for schizophrenia and autism.

    Huntington’s disease, cystic fibrosis, and muscular dystrophy are all diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy — You have the mutation? Then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism.

    “Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism,” says Osaka University Professor Toshihide Yamashita, one of the authors of the study. “Microglia contribute to the structure and function of synapse connectivities.”

    Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. They have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders.

    Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction.

    “Rare variants alter gene function but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause,” said Yamashita, who added the alanine threonine substitution was a rare variant.

    The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

    “The variant changes the region from hydrophobic to hydrophilic and destabilize Helix 8. We overexpressed the mutation in cells and found Akt signaling was disrupted,” explains Yamashita.

    According to Yamashita, the findings are the first to connect a genetic variation in microglia with neurodevelopment disorders. Moreover, he hopes that the discovery could become a basis for predictive diagnostics.

    “There is no reliable way to diagnose schizophrenia or autism in asymptomatic patients. Deeper understanding of the genetic risk factors will help us develop preventative measures.”


  4. Manipulating a single gene defines a new pathway to anxiety

    September 9, 2017 by Ashley

    From the University of Utah Health press release:

    Removing a single gene from the brains of mice and zebrafish causes these animals to become more anxious than normal. Researchers from University of Utah Health show that eliminating the gene encoding Lef1 disrupts the development of certain nerve cells in the hypothalamus that affect stress and anxiety. These results are the first implication that Lef1 functions in the hypothalamus to mediate behavior, knowledge that could prove useful for diagnosing and treating human brain disorders.

    “Anxiety is an essential behavior that is much more complex than we thought,” says first author Yuanyuan Xie, Ph.D., who led the research in collaboration with senior author Richard Dorsky, Ph.D., professor of Neurobiology and Anatomy at U of U Health. Lef1 is a component of the Wnt signaling pathway, which has roles in animal development, physiology, and disease.

    “This work is making us think about how brain structures control behavior in a different way,” Xie says. The study appears in PLOS Biology on Aug. 24.

    Humans, mice, fish, and even flies exhibit anxiety, triggering behaviors that heighten awareness. Despite its reputation, the uneasy feeling can be a good thing: in the case of zebrafish causing them to freeze in their tracks so they can hide in plain sight from predators. But being anxious at inappropriate times is counterproductive and can be a sign of unnecessary stress, a characterization that holds true not only for fish but also for people.

    When Xie and Dorsky started their investigation, they had no reason to believe that Lef1 had a specific role in anxiety. Brains of fish missing the gene were relatively normal except there were cells missing from a region called the hypothalamus. This part of the brain controls many “hard-wired” behaviors such as sleep and feeding, as well as hormone release through the pituitary gland. “Before we did the experiments we had no idea that the neurons impacted by Lef1 would preferentially impact one type of behavior,” says Dorsky.

    Tallying the genes that were most perturbed by loss of Lef1 in this brain region revealed that over 20 were involved in mood disorders like depression and anxiety. The scientists then noticed that the fish had telltale signs consistent with these disorders. The animals were reluctant to explore their environment when placed into a new tank, preferred to remain immobile at the bottom. And they grew slowly, another condition often related to elevated stress.

    Different Paths to One Behavior

    Despite the fact that brain structure and complexity vary greatly from flies to humans, Lef1 appears to mediate anxiety across species. The new study shows that unexpectedly, the gene utilizes diverse mechanisms to get the job done.

    Similar to zebrafish, mice in which Lef1 had been removed from the hypothalamus showed signs of anxiety, including being smaller and a reluctance to explore. They also had fewer brain cells in the region where Lef1 is normally present. However, the missing cells make Pro-melanin concentrating hormone (Pmch), a brain signal that was not perturbed in zebrafish. By contrast, zebrafish and Drosophila fruit flies lacking their versions of Lef1 are missing cells that make Corticotropin releasing hormone binding protein (Crhbp), and these cells were unaffected in mice.

    These results suggested that Lef1 could regulate anxiety through two different nerve cell signals. Support for this scenario was unexpectedly found in humans, where expression of Crhbp and Pmch are extremely closely linked in the hypothalamus, indicating they may actually be present in the same cells and together act downstream of Lef1 to regulate behavior.

    “When you think about genes with a conserved function you think everything that gene does must be the same in all animals. But our study shows that that isn’t necessarily true,” says Dorsky.

    The observation could explain how a gene that specifies a particular behavior can adapt to accommodate changes in brain circuitry that happen over evolutionary time. “Our results suggest that during evolution, the brain can innovate different ways to get to the same outcome,” Dorsky explains.

    The findings highlight specific sets of genes and the brain cells they affect as being involved in regulating anxiety. Future work will focus on determining whether these pathways may define a subset of human behavioral and mood disorders.


  5. Altered mitochondria associated with increased autism risk

    September 7, 2017 by Ashley

    From the Children’s Hospital of Philadelphia press release:

    Mitochondria, the tiny structures inside our cells that generate energy, may play a key role in autism spectrum disorders (ASD). A provocative new study by Children’s Hospital of Philadelphia (CHOP)’s pioneering mitochondrial medicine team suggests that variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.

    “Our findings show that differences in mitochondrial function are important in ASD,” said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. “Our team demonstrates that a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.”

    Wallace and colleagues, including Dimitra Chalkia, Larry Singh and others, published their findings in JAMA Psychiatry.

    The scientists conducted a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). The Center for Applied Genomics at CHOP had previously performed genome-wide association studies on this AGRE cohort, and partnered in this study.

    Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health.

    The current study analyzed single-nucleotide functional variants — base changes in the cohort’s mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace’s surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.

    The current study found that individuals with European haplogroups designated I, J, K, X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD.

    These mitochondrial haplogroups originated in different global geographic areas, adapted through evolution to specific regional environments. However, subsequent changes, such as migration, changes in diet, and other environmental influences, can create a mismatch between the physiology of a particular mtDNA lineage and the individual’s environment, resulting in predisposition to disease. Additional nDNA genetic factors or environmental insults may further reduce an individual’s energy output until it is insufficient to sustain normal brain development and function, resulting in disease.

    As the wiring diagram for cellular power plants, mtDNA is crucial in supplying energy to the body. The brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Wallace’s previous studies have shown that mitochondrial dysfunction can disturb the delicate balance between inhibition and excitation in brain activity — a crucial factor in ASDs and other neuropsychiatric disorders. “There may be a bioenergetic threshold,” says Wallace, adding that an individual already predisposed to ASD based on their mitochondrial haplogroup may be pushed below that threshold by the chance occurrence of additional genetic variants or environmental insults.

    The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.

    Wallace said that his team’s finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”


  6. Life at home affects kids at school, some more than others

    August 31, 2017 by Ashley

    From The Norwegian University of Science and Technology (NTNU) press release:

    Some children are more susceptible to changes than others. They carry the relationship with their parents to school with them. Genetics can help explain why.

    “When the situation changes at home for these children, the relationship with their teacher changes too,” says researcher and PhD candidate Beate W. Hygen at NTNU Social Research and the Norwegian University of Science and Technology’s (NTNU) Department of Psychology.

    This means that when things are going well at home and in the parent-child relationship, the relationship between the child and the teacher is correspondingly good. However, the teacher-child relationship deteriorates when the child’s home life becomes more difficult.

    Genetic explanation

    “Some children seem to soak up environmental factors at home. This in turn affects the relationship with the teacher. For other children, the conditions at home don’t have much influence on their relationship with the teacher,” says Hygen.

    The explanation may be partly genetic. Hygen is the first author of a recent article that considers whether certain environmental factors affect children’s social development differently depending on what kind of genetic variants the child has.

    Hygen says the researchers are finding a link between children’s susceptibility to such factors and differences in a gene that regulates how individuals are affected by oxytocin. The differences found by the researchers were located in a variant of a receptor gene called OXTR, rs 53576. You can read more about this gene at https://www.snpedia.com/index.php/Rs53576

    Oxytocin is well known, even outside research circles. It is often called the “love hormone,” because it’s triggered when we’re together with someone we love, like a romantic love or our child. But oxytocin levels also increase when a relationship appears to be in danger, so the nickname isn’t totally accurate.

    Oxytocin release, the level of oxytocin in the brain and how oxytocin affects us play a significant role in our human relationships and how we interact and engage with others.

    Study looks at ambience

    Genetic differences in how we are affected by oxytocin can thus create differences in the way we relate to each other. Biology largely determines how we behave, but this study shows that this happens in conjunction with our surroundings.

    Previous surveys that have studied conditions at home versus in school have usually primarily looked at the parents’ situation. Social learning models, Hygen says, approach the issue from a starting point of “if there’s just yelling and negativity at home, some children can take these experiences into other relationships, such as with their teachers.”

    But the researchers in this survey start with the child itself and ask the question, “How vulnerable is the child to environmental factors?”

    “The most susceptible children will bring their home situation — both good and bad — into the school setting,” says Hygen.

    The Norwegian researchers examined 652 children in two age groups: 4-to-6 year olds and 6-to-8 year olds. This data is part of the long-term Tidlig Trygg i Trondheim study conducted by the Regional Centre for Child and Youth Mental Health and Child Welfare (RKBU) of Central Norway. The survey goes into detail about the home ambience. The study aims to identify risk and protection factors for psychosocial development and development of mental health problems in children.

    The researchers also asked the children’s teachers to assess the relationships they had with the children. This last component might be a source of error in the study, the researchers said.

    Different result in the United States

    The Norwegian researchers collaborated with American researchers, who conducted the same analysis in the US. The American researchers included 559 children from different locations in the United States. They did not find the same connection between home and school relationships.

    Hygen believes she has an idea why the Norwegian and American researchers have gotten divergent results.

    “In the United States, the stability of the relationship between teacher and child is often not the same in this age group,” she says.

    Norwegian children in the 6-to-8-year age group often have the same teacher for several years. In the United States, teachers change more often, and a change in the child’s relationship with their teacher over time may therefore be due to a change of teacher, not necessarily an improvement or worsening of the relationship with the same teacher.

    So, according to Hygen, researchers are less sure whether they are able to accurately measure relationship improvement or deterioration in the US, and the more frequent teacher changes may explain why the study doesn’t capture the effect of changes in the parent-child relationship.

    The researchers also assume that the quality of teachers varies a lot more in the United States than in Norway, since the funding of the school system differs from state to state. Greater social inequalities in the United States, which can influence relationships between teachers and children, may also affect the US results.

    The study has been published in the professional journal Developmental Psychology.


  7. Blocking enzyme linked to Alzheimer’s may reverse memory loss

    August 24, 2017 by Ashley

    From the Massachusetts Institute of Technology press release:

    In the brains of Alzheimer’s patients, many of the genes required to form new memories are shut down by a genetic blockade, contributing to the cognitive decline seen in those patients.

    MIT researchers have now shown that they can reverse that memory loss in mice by interfering with the enzyme that forms the blockade. The enzyme, known as HDAC2, turns genes off by condensing them so tightly that they can’t be expressed.

    For several years, scientists and pharmaceutical companies have been trying to develop drugs that block this enzyme, but most of these drugs also block other members of the HDAC family, which can lead to toxic side effects. The MIT team has now found a way to precisely target HDAC2, by blocking its interaction with a binding partner called Sp3.

    “This is exciting because for the first time we have found a specific mechanism by which HDAC2 regulates synaptic gene expression,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the study’s senior author.

    Blocking that mechanism could offer a new way to treat memory loss in Alzheimer’s patients. In this study, the researchers used a large protein fragment to interfere with HDAC-2, but they plan to seek smaller molecules that would be easier to deploy as drugs.

    Picower Institute postdocs Hidekuni Yamakawa, Jemmie Cheng, and Jay Penney are the lead authors of the study, which appears in the Aug. 8 edition of Cell Reports.

    Memorable interactions

    In 2007, Tsai first discovered that blocking HDAC activity could reverse memory loss in mice. There are several classes of HDACs, and their primary function is to modify histones — proteins around which DNA is spooled, forming a structure called chromatin. These modifications condense chromatin, making genes in that stretch of DNA less likely to be expressed.

    Human cells have about a dozen forms of HDAC, and Tsai later found that HDAC2 is responsible for the blockade of memory-linked genes. She also discovered that HDAC2 is elevated in human Alzheimer’s patients and in several mouse models of the disease.

    “We think that HDAC2 serves as a master regulator of memory gene expression, and during Alzheimer’s disease it’s elevated so it causes an epigenetic blockade of the expression of those memory genes,” she says. “If we can remove the blockade by inhibiting HDAC2 activity or reducing HDAC2 levels, then we can remove the blockade and restore expression of all these genes necessary for learning and memory.”

    Most of the existing HDAC inhibitors that block HDAC2 also affect HDAC-1, which can have toxic side effects because HDAC1 is necessary for cell proliferation, especially in the production of white and red blood cells.

    To find a way to more specifically target HDAC2, Tsai set out to identify proteins that help the enzyme bind to genes required for memory formation. First, she analyzed gene expression data from postmortem brain samples taken from people who did not have Alzheimer’s disease, including 28 brains with high HDAC-2 levels and 35 with low levels. This search yielded more than 2,000 genes whose levels closely matched HDAC2 levels, suggesting that those genes might work in tandem with HDAC2.

    Based on what they already knew about these genes’ functions and how they physically interact with HDAC2, the researchers then picked out three of those genes for further testing. Those tests revealed that a gene called Sp3 is necessary to recruit HDAC2 to chromatin to enact its blockade of memory-linked genes.

    The researchers also examined gene expression data from postmortem brains of Alzheimer’s patients and found a nearly perfect correlation between levels of HDAC2 and sp3.

    Specific targets

    The researchers then explored what would happen if they lowered Sp3 levels in a mouse model of Alzheimer’s disease. In these mice, the same type in which they previously studied the effects of blocking HDAC2, they found that deactivating Sp3 also restored the mice’s ability to form long-term memories.

    The researchers used a type of short RNA strand to perform the genetic “knockdowns” in these experiments, but for this approach to be useful for potentially restoring memory function in human patients, scientists would likely need to develop a drug in the form of a small protein or chemical compound.

    To that end, the researchers identified the section of the HDAC2 protein that binds to Sp3. When they engineered neurons to overproduce that HDAC2 fragment, the fragment sopped up most of the available Sp3, blocking it from binding HDAC2 and releasing the blockade of memory-linked genes. Furthermore, the fragment did not interfere with cell proliferation, suggesting that this more targeted approach would not have the adverse side effects of more general HDAC inhibitors.

    The protein fragment that the researchers used to block the interaction in this study has about 90 amino acids, which would likely be too large to use as a drug, so the researchers hope to either identify a smaller segment that would still be effective, or find a chemical compound that would also disrupt the Sp3-HDAC2 interaction.

    Tsai also hopes to further investigate some of the other genes that were found to correlate with HDAC2, in hopes of identifying other drug targets. She also plans to explore whether this approach could be useful in treating other disorders that involve elevated levels of HDAC2, such as posttraumatic stress disorder.


  8. Study suggests genetic link to friendliness

    August 22, 2017 by Ashley

    From the National University of Singapore press release:

    A group of researchers from the National University of Singapore has found that CD38 and CD157 genes that regulate oxytocin, the supreme human social hormone, are associated with the sociality of young individuals. They found that young adults who have higher expression of the CD38 gene as well as differences in CD157 gene sequence are friendlier and more socially adept than others. They have more close friends and show greater social skills.

    Researchers found that CD38 and CD157 genes that regulate oxytocin, the supreme human social hormone, are associated with the sociality of young individuals.

    Why some individuals seek social engagement and friendship while others shy away, may well be dependent on the expression and sequence of two genes in their bodies.

    A group of researchers from the National University of Singapore (NUS) has found that young adults who have higher expression of the CD38 gene as well as differences in CD157 gene sequence are friendlier and more socially adept than others. They have more close friends and show greater social skills. CD38 and CD157 genes regulate the release of oxytocin, the paramount social hormone in humans involved in primary social behaviours such as pair-bonding, mating and child-rearing, to more sophisticated behaviours such as empathy, trust and generosity.

    This novel study of gene expression (i.e. how much of a particular gene is produced in the body) supports the increasing importance of the oxytocin network and its impact on shaping social and communication skills that are important for building friendships. The findings were published in the scientific journal Psychoneuroendocrinology.

    The study was conducted by Professor Richard Ebstein and recent NUS PhD graduate, Dr Anne Chong, from the Department of Psychology at NUS Faculty of Arts and Social Sciences, along with Professor Chew Soo Hong from the Faculty’s Department of Economics and Professor Lai Poh San from the Department of Paediatrics at NUS Yong Loo Lin School of Medicine.

    The team studied over 1,300 healthy young Chinese adults in Singapore in a non-clinical setting. They investigated the correlation between the expression of the CD38 gene and CD157 gene sequence, both of which have been implicated in autism studies, and an individual’s social skills as captured by three different questionnaires. These questionnaires evaluated the participants’ overall ability to engage in social relationships; their value on the importance of and interest in friendships as well as the number of close friends/confidants they have.

    Link between CD38 and CD157 genes, oxytocin and social skills

    “We believe that studying the expression of genes captures more information than simple structural studies of DNA sequence since it is the expression of genes that ultimately determine how a gene impacts our traits. Oxytocin plays an important role in these behaviours so it made good sense to our team to study the oxytocin network in relation to social skills important for friendships,” said Prof Ebstein.

    The results from the study showed that participants with higher expression of CD38 have more close friends, and this association was observed more prevalently among the male participants.

    “Male participants with the higher gene expressions displayed greater sociality such as preferring activities involving other people over being alone, better communication and empathy-related skills compared to the other participants. Meanwhile, participants with lower CD38 expression reported less social skills such as difficulty in “reading between the lines” or engaging less in social chitchat, and tend to have fewer friends,” said Dr Chong who is the first author of the study and worked under the supervision of Prof Ebstein.

    Interestingly, the researchers found that a variation in the CD157 gene sequence that was more common in autism cases in a Japanese study, was also associated with the participants’ innate interest in socialising and building relationships.

    The evidence suggests that oxytocin, and the CD38 and CD157 genes that govern its release, contribute to individual differences in social skills from one extreme of intense social involvement (i.e. many good friendships and good relationships with peers) to the other extreme of avoiding social contacts with other people that is one of the characteristics of autism. There is no cause for worry however, as the researchers note that majority of people are in between the two extremes.

    The researchers found that higher expression of the CD38 gene and differences in the CD157 gene sequence account for 14 per cent of the variance in social skills in the general population — a remarkable finding, especially since typically less than two per cent of findings in behavioural genetic association studies rely on genetic variations alone.

    “Moreover, while expressed genes can influence behaviours, our own experiences can influence the expression of genes in return. So, whether the genes are expressed to impact our behaviours or not, depend a lot on our social environments. For most people, being in healthy social environments such as having loving and supportive families, friends and colleagues would most likely lessen the effects from disadvantageous genes,” said Dr Chong.

    Findings contribute towards possible future intervention therapies or treatments for individuals with special needs

    A group of researchers from the National University of Singapore has found that CD38 and CD157 genes that regulate oxytocin, the supreme human social hormone, are associated with the sociality of young individuals. They found that young adults who have higher expression of the CD38 gene as well as differences in CD157 gene sequence are friendlier and more socially adept than others. They have more close friends and show greater social skills

    The findings from the study help deepen the understanding of the relationship between human sociability and oxytocin. By releasing the social hormone, the CD38 and CD157 genes not only regulate social life at a cellular level but also contribute to the development of human social skills important in establishing social bonds and friendship.

    “In our study, we see that an individual’s genetic makeup could only go so far as predicting one’s social predisposition but does not necessarily trigger the trait since, in the end, it is the expression of gene that determines so. This knowledge would be helpful in coming up with future intervention therapies or targeted treatments to achieve desirable outcomes for individuals with special needs,” said Prof Ebstein.

    For instance, while there is already considerable research interest in using oxytocin therapy to improve the social skills of individuals with autism, the results so far have been mixed. The findings in this study point to an alternative research direction towards treatments based on new drugs that may mimic or enhance the functions of the CD38 and CD157 genes. The researchers noted however that this line of research has yet to be explored. If proven viable, future therapies may help those clinically determined to have extreme difficulty maintaining social and working relationships with others so that they too could live a better quality of life.

    Next steps in research

    Co-led by Prof Ebstein and Prof Chew, the Behavioural and Biological Economics and the Social Sciences (B2ESS) Group at the NUS Faculty of Arts and Social Sciences has been investigating the role of genes and hormones on human behaviours, decision making, and a variety of human attitudes including empathy, impulsivity, political attitudes, religiosity and risk attitudes.

    The group is currently embarking on several behavioural economics and molecular genetics studies to investigate the impact of oxytocin on the human traits of creativity and openness to exposure, among others.


  9. Panic disorder symptoms may be tied to acid-sensing receptor

    by Ashley

    From the University of Cincinnati Academic Health Center press release:

    Panic disorder is a syndrome characterized by spontaneous and recurrent episodes of incapacitating anxiety. It typically emerges during adolescence or early adulthood and can take an exhausting emotional and physical toll on the body. Physical symptoms can include heart palpitations, sweating and/or chills, trouble breathing and dizziness, nausea and even chest pain.

    While significant progress in both diagnosis and treatment has been made with panic disorder, a lot is still not known about what triggers these panic symptoms. There is evidence that a pH inbalance disruption in the body, known as acidosis, can unexpectedly cause the panic attack.

    Researchers at the University of Cincinnati (UC) have found that a particular receptor in the body — acid-sensing T cell death associated gene-8 (TDAG8) — may have significant relevance to the physiological response in panic disorder. The research, a collaboration between Jeffrey Strawn, MD, and Renu Sah, PhD, both associate professors in the Department of Psychiatry and Behavioral Neuroscience at the UC College of Medicine, appears online in advance of publication in the journal Brain, Behavior, and Immunity.

    The TDAG8 receptor, a pH sensor, was first identified in immune cells of the body where it regulates inflammatory responses. Studies of animal models in Sah’s lab identified TDAG8 in immune cells of the brain, called microglia.

    “Although we had reported the potential relevance of TDAG8 in panic physiology in the lab, we were uncertain whether the receptor would play a role in panic disorder. It was important for us to validate this in patients with this disorder,” says Sah.

    Strawn says the UC research team then embarked on a basic science-clinical collaboration, seeking to understand the receptor’s expression in adolescents and young adults.

    “We evaluated the role of this receptor in patients with panic disorder (including adolescents who were close to the onset of panic disorder). We saw a relationship between this receptor and panic disorder symptoms, in addition to differences between patients with panic disorder and healthy individuals,” says Strawn, who is also director of the Anxiety Disorders Research program at UC.

    The study evaluated blood samples of 15 individuals between the ages 15 to 44 with a diagnosis of panic disorder and 17 healthy control participants. Anxiety symptom severity was also assessed in the study.

    The study, though small, strengthened the previous pre-clinical findings.

    “This pilot study — the first to evaluate the TDAG8 expression in patients with panic disorder — reveals significantly increased levels in patients with panic disorder, relative to their healthy control subjects,” says Strawn. “We found an association with TDAG8 and symptom severity, and we observed that there was a relationship between this receptor and treatment response in patients who had been treated with antidepressants.”

    Strawn says the findings show a direct link between increased TDAG8 expression and severity of panic disorder as well as raise the possibility that patients in treatment may reflect a “remission” of TDAG8 expression. “It will be important for additional studies to further explain the functional relevance of TDAG8 and associated inflammatory processes as well as other acid sensors in patients with panic disorder to explore the role of TDAG8 with predicting treatment response,” he says.

    Sah notes that further research could demonstrate whether altered TDAG8 is a result of a genetic variation or other factors. She also says that in future studies, perhaps drugs targeting TDAG8 or associated inflammatory responses may be developed for panic disorder.


  10. Protein involved in Alzheimer’s disease may also be implicated in cognitive abilities

    August 17, 2017 by Ashley

    From the IOS Press press release:

    Rare mutations in the amyloid precursor protein (APP) have previously been shown to be strongly associated with Alzheimer’s disease (AD). Common genetic variants in this protein may also be linked to intelligence (IQ) in children, according to recent research performed at the University of Bergen, Norway.

    Results of the research were published online in the Journal of Alzheimer’s Disease. Senior author Dr. Tetyana Zayats is a researcher at the KGJebsen Centre for Neuropsychiatric Disorders at the University of Bergen.

    The study analyzed genetic markers and IQ collected from 5,165 children in the Avon Longitudinal Study of Parents and Children. The genetic findings were followed up in the genetic data from two adult datasets (1) 17,008 cases with AD and 37,154 controls, and (2) 112,151 individuals assessed for general cognitive functioning. The function of the genetic markers was analysed using reporter assays in cells.

    Brain cells communicate via synapses containing hundreds of specialized proteins. Mutations in some of these proteins lead to dysfunctional synapses and brain diseases such as epilepsy, intellectual disability, autism or AD. Dr. Zayats and co-workers at the University of Bergen examined a subgroup of these proteins that have been implicated in synaptic plasticity and learning (the ARC complex). They found that a variation in DNA sequence within the gene encoding a member of this group of proteins, amyloid beta precursor protein (APP) was associated with non-verbal (fluid) intelligence in children, which reflects our capacity to reason and solve problems. In adults, this variation revealed association with AD, while the overall genetic variation within the APP gene itself appeared to be correlated with the efficiency of information processing (reaction time).

    “This study has potential implications for our understanding of the normal function of these synaptic proteins as well as their involvement in disease” said Dr. Zayats.

    APP encodes the amyloid-? precursor protein that forms amyloid-? — containing neuritic plaques, the accumulation of which is one of the key pathological hallmarks in AD brains. However, it is unclear how these plaques affect brain functions and whether they lead to AD.

    “Our understanding of biological processes underlying synaptic functioning could be expanded by examining human genetics throughout the lifespan as genetic influences may be the driving force behind the stability of our cognitive functioning,” Dr. Zayats commented.

    Genetic correlation between intelligence and AD has also been found in large-scale genome-wide analyses on general cognitive ability in adults. Several genes involved in general intelligence have previously reported to be associated with AD or related dementias. Such overlap has also been noted for the APP gene, where a coding variant was shown to be protective against both AD and cognitive decline in elderly.

    “While this is only an exploratory study, in-depth functional and association follow up examinations are needed,” Dr. Zayats noted. “Examining genetic overlap between cognitive functioning and AD in children — not only adults — presents us with a new avenue to further our understanding of the role of synaptic plasticity in cognitive functioning and disease.”