Posts tagged genes
Articles and news from the latest research reports.
Genetic markers ID second Alzheimer’s pathway
Researchers at Washington University School of Medicine in St. Louis have identified a new set of genetic markers for Alzheimer’s that point to a second pathway through which the disease develops.
Much of the genetic research on Alzheimer’s centers on amyloid-beta, a key component of brain plaques that build up in the brains of people with the disease.
In the new study, the scientists identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimer’s progresses and patients develop dementia. The findings may help provide targets for a different class of drugs that could be used for treatment.
The researchers report their findings online April 24 in the journal Neuron.
"We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimer’s disease,” says senior investigator Alison M. Goate, DPhil, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry. “As far as we’re aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.”
A fourth gene in the mix, APOE, had been identified long ago as a risk factor for Alzheimer’s. It has been linked to amyloid-beta, but in the new study, APOE appears to be connected to elevated levels of tau. Finding that APOE is influencing more than one pathway could help explain why the gene has such a big effect on Alzheimer’s disease risk, the researchers say.
“It appears APOE influences risk in more than one way,” says Goate, also a professor of genetics and co-director of the Hope Center for Neurological Disorders. “Some of the effects are mediated through amyloid-beta and others by tau. That suggests there are at least two ways in which the gene can influence our risk for Alzheimer’s disease.”
The new research by Goate and her colleagues is the largest genome-wide association study (GWAS) yet on tau in cerebrospinal fluid. The scientists analyzed points along the genomes of 1,269 individuals who had undergone spinal taps as part of ongoing Alzheimer’s research.
Whereas amyloid is known to collect in the brain and affect brain cells from the outside, the tau protein usually is stored inside cells. So tau usually moves into the spinal fluid when cells are damaged or die. Elevated tau has been linked to several forms of non-Alzheimer’s dementia, and first author Carlos Cruchaga, PhD, says that although amyloid plaques are a key feature of Alzheimer’s disease, it’s possible that excess tau has more to do with the dementia than plaques.
“We know there are some individuals with high levels of amyloid-beta who don’t develop Alzheimer’s disease,” says Cruchaga, an assistant professor of psychiatry. “We don’t know why that is, but perhaps it could be related to the fact that they don’t have elevated tau levels.”
In addition to APOE, the researchers found that a gene called GLIS3, and the genes TREM2 and TREML2 also affect both tau levels and Alzheimer’s risk.
Goate says she suspects changes in tau may be good predictors of advancing disease. As tau levels rise, she says people may be more likely to develop dementia. If drugs could be developed to target tau, they may prevent much of the neurodegeneration that characterizes Alzheimer’s disease and, in that way, help prevent or delay dementia.
The new research also suggests it may one day be possible to reduce Alzheimer’s risk by targeting both pathways.
“Since two mechanisms apparently exist, identifying potential drug targets along these pathways could be very useful,” she says. “If drugs that influence tau could be added to those that affect amyloid, we could potentially reduce risk through two different pathways.”
(Source: news.wustl.edu)
Research identifies co-factors critical to PTSD development
Research led by Ya-Ping Tang, MD, PhD, Associate Professor of Cell Biology and Anatomy at LSU Health Sciences Center New Orleans, has found that the action of a specific gene occurring during exposure to adolescent trauma is critical for the development of adult-onset Post-Traumatic Stress Disorder (PTSD.) The findings are published in PNAS Online Early Edition the week of April 1-5, 2013.
"This is the first study to show that a timely manipulation of a certain neurotransmitter system in the brain during the stage of trauma exposure is potentially an effective strategy to prevent the pathogenesis of PTSD," notes Dr. Tang.
The research team conducted a series of experiments using a specific strain of transgenic mice, in which the function of the gene can be suppressed, and then restored. The model combined exposure to adolescent trauma as well as an acute stressor. Clinically PTSD may occur immediately following a trauma, but in many cases, a time interval may exist between the trauma and the onset of disease. Exposure to a second stress or re-victimization can be an important causative factor. However, the researchers discovered that exposure to both adolescent trauma and to acute stress was not enough to produce consistent PTSD-like behavior. When exposure to trauma and stress was combined with the function of a specific transgene called CCKR-2, consistent PTSD-like behavior was observed in all of the behavioral tests, indicating that the development of PTSD does not depend only on the trauma itself.
As a predominant form of human anxiety disorders, PTSD affects 7.8% of people between 15-54 years in the United States. PTSD can cause feelings of hopelessness, despair and shame, employment and relationship problems, anger, and sleep difficulties. Additionally, PTSD can increase the risk of other mental health conditions including depression, substance abuse, eating disorders, and suicidal thoughts, as well as certain medical conditions including cardiovascular disease, chronic pain, autoimmune disorders, and musculoskeletal conditions.
A favored current theory of the development of anxiety disorders, including PTSD, is a gene/environment interaction. This study demonstrated that the function of the CCKR-2 gene in the brain is a cofactor, along with trauma insult, and identified a critical time window for the interaction in the development of PTSD.
"Once validated in human subjects, our findings may help target potential therapies to prevent or cure this devastating mental disorder," Dr. Tang concludes.
(Image: canstockphoto)
New Genetic Evidence Suggests a Continuum Among Neurodevelopmental and Psychiatric Disorders
A paper published this month in the prestigious medical journal The Lancet Neurology suggests that a broad spectrum of developmental and psychiatric disorders, ranging from autism and intellectual disability to schizophrenia, should be conceptualized as different manifestations of a common underlying denominator, “developmental brain dysfunction,” rather than completely independent conditions with distinct causes.
In “Developmental Brain Dysfunction: Revival and Expansion of Old Concepts Based on New Genetic Evidence,” the authors make two key points:
- Developmental disorders (such as autism and intellectual disability) and psychiatric disorders (such as schizophrenia and bipolar disorder), while considered clinically distinct, actually share many of the same underlying genetic causes. This is an example of “variable expressivity:” the same genetic variant results in different clinical signs and symptoms in different individuals.
- When quantitative measures of neuropsychological and neurobehavioral traits are studied instead of categorical diagnoses (which are either present or absent) and individuals are compared to their unaffected family members, it is possible to more accurately demonstrate the impact of genetic variants.
According to Andres Moreno De Luca, M.D., research scientist at the Autism and Developmental Medicine Institute at Geisinger Health System and article co-author, “Recent genetic studies conducted in thousands of individuals have shown that identical genetic mutations are shared among neurodevelopmental disorders that are thought to be clinically distinct. What we have seen over the past few years is that genetic mutations that were initially found in individuals with one disorder, such as intellectual disability or autism, are then identified in people with an apparently different condition like schizophrenia, epilepsy, or bipolar disorder.”
“It turns out that the genes don’t respect our diagnostic classification boundaries, but that really isn’t surprising given the overlapping symptoms and frequent co-existence of neurodevelopmental disorders,” said Scott M. Myers, M.D., autism specialist at Geisinger Health System and article co-author.
“We believe this study supports use of the term ‘developmental brain dysfunction’ or DBD, which would encompass the broad spectrum of neurodevelopmental and neuropsychiatric disorders,” said David H. Ledbetter, Ph.D., executive vice president and chief scientific officer at Geisinger Health System, and article co-author. “Additionally, it is clear that diagnostic tools such as whole genome analysis for both children and their families are essential when diagnosing and treating these disorders in order to ensure the most personalized treatment.”
An example used in the study was analysis of intelligence quotient (IQ) scores. The average IQ score in the general population is 100. Historically, the medical community has defined intellectual disability as an IQ of less than 70 (with concurrent deficits in adaptive functioning). But according to Dr. Ledbetter, there is little difference in the function of a child with an IQ of 69 versus 71, yet one may be diagnosed with a disability and the other may not.
“We know a variety of factors contribute to IQ score, including genetics, as a child’s IQ is highly correlated with that of his or her parents and siblings. Therefore, an important factor to take into consideration when interpreting IQ is family background,” said Dr. Ledbetter. “Imagine if we have a child with a genetic abnormality, but the child’s IQ is 85. Technically, we would not diagnose this child with a disability. However, if the family of this child has IQs around 130, we could consider that this child’s genetic anomaly has ‘cost’ him or her 45 IQ points – a very substantial difference.”
According to Dr. Myers, “One implication of this concept is that studies designed to investigate the causes and mechanisms of developmental brain dysfunction should focus on measurement of quantifiable neuropsychological and neurobehavioral traits across groups of individuals with different clinical diagnoses. Another is that whenever possible, individuals with a particular genetic variant or other risk factor should be compared to their unaffected family members, not just to population norms.”
Your DNA may play a significant role in determining whether or not you end up a smoker – and how easy you find it to kick the habit.
Many large studies have identified particular gene variants that are more common in smokers than other people, suggesting the they play a role in nicotine dependence.
Now an international team of researchers have used these genetic clues develop a ‘genetic risk profile’, and to see how accurate it is, they have road-tested it on the on a well known sample of Kiwis: the Dunedin Birth Cohort.
Researchers analysed data from the long-term study of 1,000 New Zealanders to identify whether individuals at high genetic risk got hooked on cigarettes more quickly as teens and whether, as adults, they had a harder time quitting.
The results, published in JAMA Psychiatry, showed that a person’s genetic risk profile did not predict whether he or she would try cigarettes. But for those who did try cigarettes, having a high-risk genetic profile predicted increased likelihood of heavy smoking and nicotine dependence.
This link was most apparent for teenagers; Among teens who tried cigarettes, those with a high-risk genetic profile were 24 percent more likely to become daily smokers by age 15 and 43 percent more likely to become pack-a-day smokers by age 18.
As adults, those with high-risk genetic profiles were 22 percent more likely to fail in their attempts at quitting.
“The effects of genetic risk seem to be limited to people who start smoking as teens,” said author Daniel Belsky, a post-doctoral research fellow at Duke University.
“This suggests there may be something special about nicotine exposure in the adolescent brain, with respect to these genetic variants.”
The authors noted that their genetic risk profile isn’t yet accurate enough to be used for targeted interventions to prevent at-risk teens smoking, but it does highlight the critical adolescent period in addiction development.
“Public health policies that make it harder for teens to become regular smokers should continue to be a focus in antismoking efforts,” Belsky said.
Which Came First, the Head or the Brain?
The sea anemone, a cnidarian, has no brain. It does have a nervous system, and its body has a clear axis, with a mouth on one side and a basal disk on the other. However, there is no organized collection of neurons comparable to the kind of brain found in bilaterians, animals that have both a bilateral symmetry and a top and bottom. (Most animals except sponges, cnidarians, and a few other phyla are bilaterians.) So an interesting evolutionary question is, which came first, the head or the brain? Do animals such as sea anemones, which lack a brain, have something akin to a head?
In this issue of PLOS Biology, Chiara Sinigaglia and colleagues report that at least some developmental pathways seen in cnidarians share a common lineage with head and brain development in bilaterians. It might seem intuitive to expect to find genes involved in brain development around the mouth of the anemone, and previous work has suggested that the oral region in cnidarians corresponds to the head region of bilaterians. However, there has been debate over whether the oral or aboral pole of cnidarians is analogous to the anterior pole of bilaterians. At the start of its life cycle a sea anemone exists as a free swimming planula, which then attaches to a surface and becomes a sea anemone. That free-swimming phase contains an apical tuft, a sensory structure at the front of the swimming animal’s body. The apical tuft is the part that attaches and becomes the aboral pole (the part distal from the mouth) of the adult anemone.
To test whether genetic expression in the aboral pole of cnidarians does in fact resemble the head patterning seen in bilaterians, the researchers analyzed gene expression in Nematostella vectensis, a sea anemone found in estuaries and bays. They focused on the six3 and FoxQ2 transcription factors, as these genes are known to regulate development of the anterior-posterior axis in bilaterian species. (six3 knockout mice, for example, fail to develop a forebrain, and in humans, six3 is known to regulate the development of forebrain and eyes.)
The N. vectensis genome contains one gene from the six3/6 group and four foxQ2 genes. Sinigaglia and colleagues found that Nvsix3/6 and one of the foxQ2 genes, NvFoxQ2a, were expressed predominantly on the aboral pole of the developing cnidarian but, after gastrulation, were excluded from a small spot in that region (NvSix3/6 was also expressed in a small number of other cells of the planula that resembled neurons). Because of this, the authors call NvSix3/6 and NvFoQ2a “ring genes”, and genes that are then expressed in that spot “spot genes.” The spot then develops into the apical tuft.
Through knockdown and rescue experiments, the researchers demonstrate that NvSix3/6 is required for the development of the aboral region; without it, the expression of spot genes is reduced or eliminated and the apical tuft of the planula doesn’t form. This suggests that development of the region distal from the cnidarian mouth appears to parallel the development of the bilaterian head.
This research demonstrates that at least a subset of the genes that cause head and brain formation in bilaterians are also differentially expressed in the aboral region of the sea urchin. The expression patterns are not identical to those in all bilaterians; however, the similarities suggest that the patterns of gene expression arose in an ancestor common to bilaterians and cnidarians, and that the process was then modified in bilaterians to produce a brain. So to answer the evolutionary question posed above, it seems that the developmental module that produces a head came first.
Researchers form new nerve cells – directly in the brain
The field of cell therapy, which aims to form new cells in the body in order to cure disease, has taken another important step in the development towards new treatments. A new report from researchers at Lund University in Sweden shows that it is possible to re-programme other cells to become nerve cells, directly in the brain.
Two years ago, researchers in Lund were the first in the world to re-programme human skin cells, known as fibroblasts, to dopamine-producing nerve cells – without taking a detour via the stem cell stage. The research group has now gone a step further and shown that it is possible to re-programme both skin cells and support cells directly to nerve cells, in place in the brain.
“The findings are the first important evidence that it is possible to re-programme other cells to become nerve cells inside the brain”, said Malin Parmar, research group leader and Reader in Neurobiology.
The researchers used genes designed to be activated or de-activated using a drug. The genes were inserted into two types of human cells: fibroblasts and glia cells – support cells that are naturally present in the brain. Once the researchers had transplanted the cells into the brains of rats, the genes were activated using a drug in the animals’ drinking water. The cells then began their transformation into nerve cells.
In a separate experiment on mice, where similar genes were injected into the mice’s brains, the research group also succeeded in re-programming the mice’s own glia cells to become nerve cells.
“The research findings have the potential to open the way for alternatives to cell transplants in the future, which would remove previous obstacles to research, such as the difficulty of getting the brain to accept foreign cells, and the risk of tumour development”, said Malin Parmar.
All in all, the new technique of direct re-programming in the brain could open up new possibilities to more effectively replace dying brain cells in conditions such as Parkinson’s disease.
“We are now developing the technique so that it can be used to create new nerve cells that replace the function of damaged cells. Being able to carry out the re-programming in vivo makes it possible to imagine a future in which we form new cells directly in the human brain, without taking a detour via cell cultures and transplants”, concluded Malin Parmar.
The research article is entitled ‘Generation of induced neurons via direct conversion in vivo’ and has been published in the Proceedings of the National Academy of Science (PNAS)
(Source: lunduniversity.lu.se)
New mechanism for long-term memory formation discovered
UC Irvine neurobiologists have found a novel molecular mechanism that helps trigger the formation of long-term memory. The researchers believe the discovery of this mechanism adds another piece to the puzzle in the ongoing effort to uncover the mysteries of memory and, potentially, certain intellectual disabilities.
In a study led by Marcelo Wood of UC Irvine’s Center for the Neurobiology of Learning & Memory, the team investigated the role of this mechanism – a gene designated Baf53b – in long-term memory formation. Baf53b is one of several proteins making up a molecular complex called nBAF.
Mutations in the proteins of the nBAF complex have been linked to several intellectual disorders, including Coffin-Siris syndrome, Nicolaides-Baraitser syndrome and sporadic autism. One of the key questions the researchers addressed is how mutations in components of the nBAF complex lead to cognitive impairments.
In their study, Wood and his colleagues used mice bred with mutations in Baf53b. While this genetic modification did not affect the mice’s ability to learn, it did notably inhibit long-term memories from forming and severely impaired synaptic function.
“These findings present a whole new way to look at how long-term memories form,” said Wood, associate professor of neurobiology & behavior. “They also provide a mechanism by which mutations in the proteins of the nBAF complex may underlie the development of intellectual disability disorders characterized by significant cognitive impairments.”
How does this mechanism regulate gene expression required for long-term memory formation? Most genes are tightly packaged by a chromatin structure – chromatin being what compacts DNA so that it fits inside the nucleus of a cell. That compaction mechanism represses gene expression. Baf53b, and the nBAF complex, physically open the chromatin structure so specific genes required for long-term memory formation are turned on. The mutated forms of Baf53b did not allow for this necessary gene expression.
“The results from this study reveal a powerful new mechanism that increases our understanding of how genes are regulated for memory formation,” Wood said. “Our next step is to identify the key genes the nBAF complex regulates. With that information, we can begin to understand what can go wrong in intellectual disability disorders, which paves a path toward possible therapeutics.”
Findings appear online today in Nature Neuroscience.
The Mysterious GRIN3A and the Cause of Schizophrenia
Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for chemicals that might be related to the hallucinogens phencyclidine (PCP) or lysergic acid diethylamide (LSD), which could explain the emergence of psychotic symptoms in schizophrenia. This “auto-intoxication” hypothesis led investigators on a wild goose chase where substances, including the “Pink Spot” and the “Frohman Factor”, were isolated from people with schizophrenia and implicated in their illness, but these findings were later discredited.
The mysterious GRIN3A is a new version of the hunt for an intrinsic mechanism that produces schizophrenia-like symptoms. GRIN3A is a gene that codes for the GluN3A subunit of the N-methyl-D-aspartate-type (NMDA) receptor, a target for the neurotransmitter glutamate in the brain. Functional NMDA receptors usually have two GluN1 subunits and two GluN2 subunits. The ability of glutamate to activate these receptors is blocked by PCP and the anesthetic/hallucinogen, ketamine. When the GluN3A subunit is incorporated, it prevents the NMDA receptor from being activated by glutamate, almost as if the receptor had been blocked by PCP.
It is unclear why the brain needs this mechanism for normal brain development and function, hence the mystery surrounding GRIN3A. One piece of evidence supporting a link between GluN3A and schizophrenia is the finding that GluN3A levels are elevated in the post-mortem brain tissue from people who had been diagnosed with schizophrenia.
In this issue of Biological Psychiatry, Japanese researchers led by Dr. Takeo Yoshikawa provide new support for this hypothesis by implicating variation in GRIN3A in the heritable risk for schizophrenia.
Schizophrenia is thought to have a substantial genetic background which is, to some extent, population-specific. Genome-wide searches have revealed many common genomic variants with weak effects, but the remaining “missing heritability” is largely unknown. Scientists theorize that it may be partly explained by rare variants with large effect.
To identify genetic variants with larger effect sizes, Yoshikawa and his colleagues examined genetic data from several Asian populations. They identified a rare variant in GRIN3A with study-wide significance.
"This discovery is important, because the ‘NMDA receptor hypothesis’ for schizophrenia is a common disease model," said Yoshikawa. "We propose a novel point of therapeutic intervention in the NMDA receptor signaling system for schizophrenia."
Dr. John Krystal, Editor of Biological Psychiatry, commented, “The notion that a genetic trait that acts like PCP in the brain produces schizophrenia is a very attractive but over-simplistic hypothesis. It is that the biology of schizophrenia is much more complicated than this single factor. Nonetheless, perhaps this study of GRIN3A brings us another step closer to understanding glutamate abnormalities in schizophrenia.”
(Source: alphagalileo.org)
Mutations in VCP gene implicated in a number of neurodegenerative diseases
New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).
Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.
In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.
The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.
Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.
In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.
“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome .
Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”
Virus and genes involved in causation of schizophrenia
For the first time, an international team of researchers has found that a combination of a particular virus in the mother and a specific gene variant in the child increases the risk of the child developing schizophrenia.
Viruses and genes interact in a way that may increase the risk of developing schizophrenia significantly. This happens already in the developing foetus.
An international team of scientists led by Aarhus University, Denmark, has made this discovery. As the first in the world, they scanned the entire genome of hundreds of sick and healthy people to see if there is an interaction between genes and a very common virus - cytomegalovirus - and to see whether the interaction influences the risk of developing schizophrenia.
And it does.
Women that have been infected by the virus - and around 70% has - will have a statistically significant increased risk of giving birth to a child who later develops schizophrenia if the child also has the aforementioned gene variant. This variant is found in 15 percent. The risk is five times higher than usual, the researchers report in Molecular Psychiatry.
No cause for alarm
People infected with cytomegalovirus most often do not know it, as the infection by the virus, which belongs to the herpes virus family, is usually very mild. But the researchers stress that there is no cause for alarm - even if both risk factors are present in mother and child, there may be a variety of other factors that prevents disease development in the child.
But as schizophrenia affects 1 per cent of the global population, this new knowledge is very important.
"In the longer term, the development of an effective vaccine against cytomegalovirus may help to prevent many cases of schizophrenia," says Professor of Medical Genetics at Aarhus University, Anders Børglum.
"And our discovery emphasizes that mental disorders such as schizophrenia may arise in the context of an interaction between genes and biological environmental factors very early in life."
(Source: eurekalert.org)