Posts tagged genetics
Articles and news from the latest research reports.
Effects of Chronic Stress Can be Traced to Your Genes
New research shows that chronic stress changes gene activity in immune cells before they reach the bloodstream. With these changes, the cells are primed to fight an infection or trauma that doesn’t actually exist, leading to an overabundance of the inflammation that is linked to many health problems.
This is not just any stress, but repeated stress that triggers the sympathetic nervous system, commonly known as the fight-or-flight response, and stimulates the production of new blood cells. While this response is important for survival, prolonged activation over an extended period of time can have negative effects on health.
A study in animals showed that this type of chronic stress changes the activation, or expression, of genes in immune cells before they are released from the bone marrow. Genes that lead to inflammation are expressed at higher-than-normal levels, while the activation of genes that might suppress inflammation is diminished.
Ohio State University scientists made this discovery in a study of mice. Their colleagues from other institutions, testing blood samples from humans living in poor socioeconomic conditions, found that similarly primed immune cells were present in these chronically stressed people as well.
“The cells share many of the same characteristics in terms of their response to stress,” said John Sheridan, professor of oral biology in the College of Dentistry and associate director of Ohio State’s Institute for Behavioral Medicine Research (IBMR), and co-lead author of the study. “There is a stress-induced alteration in the bone marrow in both our mouse model and in chronically stressed humans that selects for a cell that’s going to be pro-inflammatory.
“So what this suggests is that if you’re working for a really bad boss over a long period of time, that experience may play out at the level of gene expression in your immune system.”
The findings suggest that drugs acting on the central nervous system to treat mood disorders might be supplemented with medications targeting other parts of the body to protect health in the context of chronic social stress.
Steven Cole, a professor of medicine and a member of the Cousins Center for Psychoneuroimmunology at UCLA, is a co-corresponding author of the study. The research is published in a recent issue of the journal Proceedings of the National Academy of Sciences.
The mind-body connection is well established, and research has confirmed that stress is associated with health problems. But the inner workings of that association – exactly how stress can harm health – are still under investigation.
Sheridan and colleagues have been studying the same mouse model for a decade to reveal how chronic stress – and specifically stress associated with social defeat – changes the brain and body in ways that affect behavior and health.
The mice are repeatedly subjected to stress that might resemble a person’s response to persistent life stressors. In this model, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours at a time. This elicits a “fight or flight” response in the resident mice as they are repeatedly defeated by the intruder.
“These mice are chronically in that state, so our research question is, ‘What happens when you stimulate the sympathetic nervous system over and over and over, or continuously?’ We see deleterious consequences to that,” Sheridan said.
Under normal conditions, the bone marrow in animals and humans is making and releasing billions of red blood cells every day, as well as a variety of white blood cells that constitute the immune system. Sheridan and colleagues already knew from previous work that stress skews this process so that the white blood cells produced in the bone marrow are more inflammatory than normal upon their release – as if they are ready to defend the body against an external threat.
A typical immune response to a pathogen or other foreign body requires some inflammation, which is generated with the help of immune cells. But when inflammation is excessive and has no protective or healing role, the condition can lead to an increased risk for cardiovascular diseases, diabetes and obesity, as well as other disorders.
In this work, the researchers compared cells circulating in the blood of mice that had experienced repeated social defeat to cells from control mice that were not stressed. The stressed mice had an average fourfold increase in the frequency of immune cells in their blood and spleen compared to the normal mice.
Genome-wide analysis of these cells that had traveled to the spleen in the stressed mice showed that almost 3,000 genes were expressed at different levels – both higher and lower – compared to the genes in the control mice. Many of the 1,142 up-regulated genes in the immune cells of stressed mice gave the cells the power to become inflammatory rapidly and efficiently.
“There is no traditional viral or bacterial challenge – we’re generating the challenge via a psychological response,” said study first author Nicole Powell, a research scientist in oral biology at Ohio State. “This study provides a nice mechanism for how psychology impacts biology. Other studies have indicated that these cells are more inflammatory; our work shows that these cells are primed at the level of the gene, and it’s directly due to the sympathetic nervous system.”
The researchers confirmed that the sympathetic nervous system was activated by showing that a beta blocker reduced symptoms associated with chronic stress. The beta receptors that were turned off by this intervention are major participants in the sympathetic nervous system response.
Meanwhile, UCLA’s Cole performs specialized statistical analyses of genome function to determine how people’s perception of their surroundings affects their biology. He and colleagues analyzed blood samples both from Sheridan’s mice and from healthy young adult humans whose socioeconomic status had been previously characterized as either high or low.
The human analysis identified differing levels of expression of 387 genes between the low- and high-socioeconomic status adults – and as in the mice, the up-regulated genes were pro-inflammatory in nature. The researchers also noted that almost a third of the genes with altered expression levels in immune cells from chronically stressed humans were the same genes differentially expressed in mice that had experienced repeated social defeat – a much higher similarity than would occur by chance.
This same pro-inflammatory immune-cell profile has been seen in research on parents of children with cancer.
“What we see in this study is a convergence of animal and human data showing similar genomic responses to adversity,” Cole said. “The molecular information from animal research integrates nicely with the human findings in showing a significant up-regulation of pro-inflammatory genes as a consequence of stress – and not just experimental stress, but authentic environmental stressors humans experience in everyday life.”
Study finds a patchwork of genetic variation in the brain
It was once thought that each cell in a person’s body possesses the same DNA code and that the particular way the genome is read imparts cell function and defines the individual. For many cell types in our bodies, however, that is an oversimplification. Studies of neuronal genomes published in the past decade have turned up extra or missing chromosomes, or pieces of DNA that can copy and paste themselves throughout the genomes.
The only way to know for sure that neurons from the same person harbor unique DNA is by profiling the genomes of single cells instead of bulk cell populations, the latter of which produce an average. Now, using single-cell sequencing, Salk Institute researchers and their collaborators have shown that the genomic structures of individual neurons differ from each other even more than expected. The findings were published November 1, 2013, in Science.
"Contrary to what we once thought, the genetic makeup of neurons in the brain aren’t identical, but are made up of a patchwork of DNA," says corresponding author Fred Gage, Salk’s Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
In the study, led by Mike McConnell, a former junior fellow in the Crick-Jacobs Center for Theoretical and Computational Biology at the Salk, researchers isolated about 100 neurons from three people posthumously. The scientists took a high-level view of the entire genome—looking for large deletions and duplications of DNA called copy number variations or CNVs—and found that as many as 41 percent of neurons had at least one unique, massive CNV that arose spontaneously, meaning it wasn’t passed down from a parent. The CNVs are spread throughout the genome, the team found.
The miniscule amount of DNA in a single cell has to be chemically amplified many times before it can be sequenced. This process is technically challenging, so the team spent a year ruling out potential sources of error in the process.
"A good bit of our study was doing control experiments to show that this is not an artifact," says Gage. "We had to do that because this was such a surprise—finding out that individual neurons in your brain have different DNA content."
The group found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people. Scientists routinely use such induced pluripotent stem cells (iPSCs) to study living neurons in a culture dish. Because iPSCs are derived from single skin cells, one might expect their genomes to be the same.
"The surprising thing is that they’re not," says Gage. "There are quite a few unique deletions and amplifications in the genomes of neurons derived from one iPSC line."
Interestingly, the skin cells themselves are genetically different, though not nearly as much as the neurons. This finding, along with the fact that the neurons had unique CNVs, suggests that the genetic changes occur later in development and are not inherited from parents or passed to offspring.
It makes sense that neurons have more diverse genomes than skin cells do, says McConnell, who is now an assistant professor of biochemistry and molecular genetics at the University of Virginia School of Medicine in Charlottesville. “The thing about neurons is that, unlike skin cells, they don’t turn over, and they interact with each other,” he says. “They form these big complex circuits, where one cell that has CNVs that make it different can potentially have network-wide influence in a brain.”
Spontaneously occurring CNVs have also been linked to risk for brain disorders such as schizophrenia and autism, but those studies usually pool many blood cells. As a result, the CNVs uncovered in those studies affect many if not all cells, which suggests that they arise early in development.
The purpose of CNVs in the healthy brain is still unclear, but researchers have some ideas. The modifications might help people adapt to new surroundings encountered over a lifetime, or they might help us survive a massive viral infection. The scientists are working out ways to alter genomic variability in iPSC-derived neurons and challenge them in specific ways in the culture dish.
Cells with different genomes probably produce unique RNA and then proteins. However, for now, only one sequencing technology can be applied to a single cell.
"If and when more than one method can be applied to a cell, we will be able to see whether cells with different genomes have different transcriptomes (the collection of all the RNA in a cell) in predictable ways," says McConnell.
In addition, it will be necessary to sequence many more cells, and in particular, more cell types, notes corresponding author Ira Hall, an associate professor of biochemistry and molecular genetics at the University of Virginia. “There’s a lot more work to do to really understand to what level we think the things we’ve found are neuron-specific or associated with different parameters like age or genotype,” he says.
(Source: salk.edu)
Gene Found To Foster Synapse Formation In The Brain
Researchers at Johns Hopkins say they have found that a gene already implicated in human speech disorders and epilepsy is also needed for vocalizations and synapse formation in mice. The finding, they say, adds to scientific understanding of how language develops, as well as the way synapses — the connections among brain cells that enable us to think — are formed. A description of their experiments appears in Science Express on Oct. 31.
A group led by Richard Huganir, Ph.D., director of the Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, set out to investigate genes involved in synapse formation. Gek-Ming Sia, Ph.D., a research associate in Huganir’s laboratory, first screened hundreds of human genes for their effects on lab-grown mouse brain cells. When one gene, SRPX2, was turned up higher than normal, it caused the brain cells to erupt with new synapses, Sia found.
When Huganir’s team injected fetal mice with an SRPX2-blocking compound, the mice showed fewer synapses than normal mice even as adults, the researchers found. In addition, when SRPX2-deficient mouse pups were separated from their mothers, they did not emit high-pitched distress calls as other pups do, indicating they lacked the rodent equivalent of early language ability.
Other researchers’ analyses of the human genome have found that mutations in SRPX2 are associated with language disorders and epilepsy, and when Huganir’s team injected the human SRPX2 with the same mutations into the fetal mice, they also had deficits in their vocalization as young pups.
Another research group at Institut de Neurobiologie de la Méditerranée in France had previously shown that SRPX2 interacts with FoxP2, a gene that has gained wide attention for its apparently crucial role in language ability.
Huganir’s team confirmed this, showing that FoxP2 controls how much protein the SRPX2 gene makes and may affect language in this way. “FoxP2 is famous for its role in language, but it’s actually involved in other functions as well,” Huganir comments. “SRPX2 appears to be more specialized to language ability.” Huganir suspects that the gene may also be involved in autism, since autistic patients often have language impairments, and the condition has been linked to defects in synapse formation.
This study is only the beginning of teasing out how SRPX2 acts on the brain, Sia says. “We’d like to find out what other proteins it acts on, and how exactly it regulates synapses and enables language development.”
Rare Childhood Disease May Hold Clues to Treating Alzheimer’s and Parkinson’s
Scientists at Rutgers University studying the cause of a rare childhood disease that leaves children unable to walk by adolescence say new findings may provide clues to understanding more common neurodegenerative diseases like Alzheimer’s and Parkinson’s and developing better tools to treat them.
Courtesy of A-T Children’s Project: Andrew, 14, who has A-T disease with his brother, Brendan, 12, who did not inherit the rare childhood neurodegenerative disorder.
In today’s online edition of Nature Neuroscience, professors Karl Herrup, Ronald Hart and Jiali Li in the Department of Cell Biology and Neuroscience, and Alexander Kusnecov, associate professor in behavioral and systems neuroscience in the Department of Psychology, provide new information about A-T disease, a rare genetic childhood disorder that occurs in an estimated 1 in 40,000 births.
Children born with A-T disease have mutations in both of their copies of the ATM gene and cannot make normal ATM protein. This leads to problems in movement, coordination, equilibrium and muscle control as well as a number of other deficiencies outside the nervous system.
Using mouse and human brain tissue studies, Rutgers researchers found that without ATM, the levels of a regulatory protein known as EZH2 go up. Looking through the characteristics of A-T disease in cells in tissue culture and in brain samples from both humans and mice with ATM mutation, they found that the increase in EZH2 was a major contributing factor to the neuromuscular problems caused by A-T.
“We hope that this work will lead to new therapies to prevent symptoms in those with A-T disease,” says Hart. “But on a larger level, this research provides a strong clue toward understanding more common neurodegenerative disorders that may use similar pathways. “It is a theme that has not yet been examined.”
While the EZH2 protein has been shown to help determine whether genes get turned on or off, altering the body’s ability to perform biological functions, necessary for maintaining good health, the Rutgers study is the first time this protein – which can cause adverse health effects if there is too much of it – has been looked at in the mature nerve cells of the brain.
By reducing the excess EZH2 protein that accumulated in mice genetically engineered with A-T disease, and creating a better protein balance within the nerve cells, Rutgers scientists found that mice exhibited improved muscle control, movement and coordination.
In the study, mutant mice that had A-T disease and increased levels of EZH2 were “cured” when this excess EZH2 protein was reduced. The treated mice were able to stay on a rotating rod without falling off almost as long as the mice that did not have A-T disease. By contrast, untreated A-T animals lost their balance and fell off the device almost immediately. The mice were also studied in an open area setting. While the treated A-T mice and normal mice explored a wide area of the open field, the A-T mice, with their excess EZH2 protein, were not as adventurous and stayed behind.
Rutgers scientists say the implications of these findings now need to be validated in a clinical setting. They have begun working with the A-T Clinical Center at Johns Hopkins University, collecting blood samples from children with the disease as well as their parents who carry the genes in order to reprogram them into stem cells. This will allow scientists to create human neurons like those in A-T patients and study the mechanisms that lead from ATM mutations to nerve cell disease in more detail.
The hope is that this new information can be used to develop therapeutic drugs that may result in better neuromuscular control and coordination for those with A-T disease. In addition, the scientists will work to determine whether the EZH2 protein plays a role in other more common neurodegenerative diseases, like Parkinson’s and Alzheimer’s and could offer a target for developing drugs to treat those brain disorders.
“What is interesting about human health and this research in particular is that it illustrates how a disease that is thought of as 100 percent genetic, actually has a component that is sensitive to the environment,” says Herrup, lead author of the study.
(Source: news.rutgers.edu)
NIH-supported study identifies 11 new Alzheimer’s disease risk genes
An international group of researchers has identified 11 new genes that offer important new insights into the disease pathways involved in Alzheimer’s disease. The highly collaborative effort involved scanning the DNA of over 74,000 volunteers—the largest genetic analysis yet conducted in Alzheimer’s research—to discover new genetic risk factors linked to late-onset Alzheimer’s disease, the most common form of the disorder.
By confirming or suggesting new processes that may influence Alzheimer’s disease development—such as inflammation and synaptic function—the findings point to possible targets for the development of drugs aimed directly at prevention or delaying disease progression.
Supported in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, the International Genomic Alzheimer’s Project (IGAP) reported its findings online in Nature Genetics on Oct. 27, 2013. IGAP is comprised of four consortia in the United States and Europe which have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting the subtle gene variants involved in Alzheimer’s and defining how the molecular mechanisms influence disease onset and progression.
"Collaboration among researchers is key to discerning the genetic factors contributing to the risk of developing Alzheimer’s disease," said Richard J. Hodes, M.D., director of the NIA. "We are tremendously encouraged by the speed and scientific rigor with which IGAP and other genetic consortia are advancing our understanding."
The search for late-onset Alzheimer’s risk factor genes had taken considerable time, until the development of GWAS and other techniques. Until 2009, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been identified as a known risk factor. Since then, prior to today’s discovery, the list of known gene risk factors had grown to include other players—PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1 and TREM2.
IGAP’s discovery reported today of 11 new genes strengthens evidence about the involvement of certain pathways in the disease, such as the role of the SORL1 gene in the abnormal accumulation of amyloid protein in the brain, , a hallmark of Alzheimer’s disease. It also offers new gene risk factors that may influence several cell functions, to include the ability of microglial cells to respond to inflammation.
The researchers identified the new genes by analyzing previously studied and newly collected DNA data from 74,076 older volunteers with Alzheimer’s and those free of the disorder from 15 countries. The new genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2 and CASS4) add to a growing list of gene variants associated with onset and progression of late-onset Alzheimer’s. Researchers will continue to explore the roles played by these genes, to include:
- How SORL1 and CASS4 influence amyloid, and how CASS4 and FERMT2 affect tau, another protein hallmark of Alzheimer’s disease
- How inflammation is influenced by HLA-DRB5/DRB1, INPP5D, MEF2C, CR1 and TREM2
- How SORL1affects lipid transport and endocytosis (or protein sorting within cells)
- How MEF2C and PTK2B influence synaptic function in the hippocampus, a brain region important to learning and memory
- How CASS4, CELF1, NME8 and INPP5 affect brain cell function
The study also brought to light another 13 variants that merit further analysis.
"Interestingly, we found that several of these newly identified genes are implicated in a number of pathways," said Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, who directs one of the major IGAP consortia. "Alzheimer’s is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play. I look forward to our continued collaboration to find out more about these—and perhaps other—genes."
(Image: National Institute on Aging)
Lou Gehrig’s Disease: From Patient Stem Cells to Potential Treatment Strategy in One Study
Although the technology has existed for just a few years, scientists increasingly use “disease in a dish” models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig’s disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.
After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing “proof of concept” for a new therapeutic strategy – an important step in moving research findings into clinical trials.
The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig’s disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and “treated,” suggesting a potential future therapy all in a single study.
"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease’s genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai’s Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article’s senior author.
Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells – cells derived from a patient’s own skin samples and “sent back in time” through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.
The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai’s Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article’s first author and one of several institute researchers who participated in the study.
"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer’s and Parkinson’s disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."
Frontotemporal lobar degeneration is a brain disorder that typically leads to dementia and sometimes occurs in tandem with ALS.
The researchers found that the genetic defect of C9ORF72 may cause disease because it changes the structure of ribonucleic acid (RNA) coming from the gene, creating an abnormal buildup of a repeated set of nucleotides, the basic components of RNA.
"We think this buildup of thousands of copies of the repeated sequence GGGGCC in the nucleus of patients’ cells may become "toxic" by altering the normal behavior of other genes in motor neurons," Baloh said. "Because our studies supported the toxic RNA mechanism theory, we used two small segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and degrade the toxic RNA. One ASO knocked down overall C9ORF72 levels. The other knocked down the toxic RNA coming from the gene without suppressing overall gene expression levels. The absence of such potentially toxic RNA, and no evidence of detrimental effect on the motor neurons, provides a strong basis for using this strategy to treat patients suffering from these diseases."
Researchers from another institution recently led a phase one trial of a similar ASO strategy to treat ALS caused by a different genetic mutation and reportedly uncovered no safety issues.
(Source: cedars-sinai.edu)
Yeast, human stem cells drive discovery of new Parkinson’s disease drug targets
Using a discovery platform whose components range from yeast cells to human stem cells, Whitehead Institute scientists have identified a novel Parkinson’s disease drug target and a compound capable of repairing neurons derived from Parkinson’s patients.
The platform—whose effectiveness is described in dual papers published online this week in the journal Science—could accelerate the discovery of drug candidates that address the underlying pathology of Parkinson’s and other neurodegenerative diseases. Today, no such drugs exist.
Parkinson’s disease (PD) and such neurodegenerative diseases as Huntington’s and Alzheimer’s are characterized by protein misfolding, resulting in toxic accumulations of proteins in the cells of the central nervous system. Cellular buildup of the protein alpha-synuclein, for example, has long been associated with PD, making this protein a seemingly appropriate target for therapeutic intervention.
In the search for compounds that might alter a protein’s behavior or function—such as that of alpha-synuclein—drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they’re moved from the in vitro environment into a living setting.
To overcome this limitation, the lab of Whitehead Member Susan Lindquist has turned to phenotypic screens in which candidate compounds are studied within a living system. In Lindquist’s lab, yeast cells—which share the core cell biology of human cells —serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.
“Phenotypic screens are probably underutilized for identifying drug targets and potential compounds,” says Daniel Tardiff, a scientist in the Lindquist lab and lead author of one of the Science papers. “Here, we let the yeast tell us what is a good target. We let a living cell tell us what’s critical for reversing alpha-synuclein toxicity.”
In a screen of nearly 200,000 compounds, Tardiff and collaborators identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. Enabled by the chemistry provided by Nate Jui in the Buchwald lab at MIT, Tardiff found that the compound was working by restoring functions mediated by a cellular protein critical for trafficking that was previously thought to be “undruggable.”
But would these findings apply in human cells? To answer that question, husband-and-wife team Chee-Yeun Chung and Vikram Khurana led the second study published in Science to examine neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson’s patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. To ensure that any pathology developed in the cultured neurons could be attributed solely to the genetic defect, the researchers also derived control neurons from iPS cells in which the mutation had been corrected.
Chung and Khurana used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens in Tardiff’s study reversed the damage in these neurons.
“It was remarkable that the compound rescued yeast cells and patient neurons in similar ways and through the same target—a target we would not have identified without yeast genetics to guide us,” says Khurana, a postdoctoral scientist in the Lindquist lab and a neurologist at Massachusetts General Hospital who recruited patients for participation in this research. Khurana believes that the abnormalities discovered occur in the early stages of disease. If so, successful manipulation of the targets identified here might help slow or even prevent disease progression.
For the researchers involved, these findings are a bit of surprise. Because neurodegenerative disorders like PD are largely diseases of aging, modeling them in a culture dish using neurons grown from iPS cells has been thought to be exceedingly difficult, if not impossible.
“Many, ourselves included, were skeptical that we could find any important pathologies for a neurodegenerative disorder by reprogramming patient cells,” says Chung, a Senior Research Scientist in the Lindquist lab. “Critically, we also validated these pathologies in post-mortem brains, so we’re quite confident these are relevant for the disease.”
Next steps for these scientists include chemically optimizing the compound identified and testing it in animal models. Moreover, they are convinced that this yeast-human stem cell discovery platform could be applied to other neurodegenerative diseases for which yeast models have been developed.
“Using yeast genetics to identify a compound and its mechanism of action against the fundamental pathology of a disease illustrates the power of the system we’ve built,” says Lindquist, who is also professor of biology at MIT and a Howard Hughes Medical Institute investigator. “It’s critical that we continue to leverage this power because as we reduce the rate at which people are dying from cancer and heart disease, the burden of these dreaded neurodegenerative diseases is going to rise. It’s inevitable.”
Genetic analysis reveals insights into the genetic architecture of OCD, Tourette syndrome
An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS), providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders. Their report is being published in the October issue of the open-access journal PLOS Genetics.
"Both TS and OCD appear to have a genetic architecture of many different genes – perhaps hundreds in each person – acting in concert to cause disease,” says Jeremiah Scharf, MD, PhD, of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology, senior corresponding author of the report. “By directly comparing and contrasting both disorders, we found that OCD heritability appears to be concentrated in particular chromosomes – particularly chromosome 15 – while TS heritability is spread across many different chromosomes.”
An anxiety disorder characterized by obsessions and compulsions that disrupt the lives of patients, OCD is the fourth most common psychiatric illness. TS is a chronic disorder characterized by motor and vocal tics that usually begins in childhood and is often accompanied by conditions like OCD or attention-deficit hyperactivity disorder. Both conditions have been considered to be heritable, since they are known to often recur in close relatives of affected individuals, but identifying specific genes that confer risk has been challenging.
Two reports published last year in the journal Molecular Psychiatry (1, 2), with leadership from Scharf and several co-authors of the current study, described genome-wide association studies (GWAS) of thousands of affected individuals and controls. While those studies identified several gene variants that appeared to increase the risk of each disorder, none of the associations were strong enough to meet the strict standards of genome-wide significance. Since the GWAS approach is designed to identify relatively common gene variants and it has been proposed that OCD and TS might be influenced by a number of rare variants, the research team adopted a different method. Called genome-wide complex trait analysis (GCTA), the approach allows simultaneous comparision of genetic variation across the entire genome, rather than the GWAS method of testing sites one at a time, as well as estimating the proportion of disease heritability caused by rare and common variants.
"Trying to find a single causative gene for diseases with a complex genetic background is like looking for the proverbial needle in a haystack,” says Lea Davis, PhD, of the section of Genetic Medicine at the University of Chicago, co-corresponding author of the PLOS Genetics report. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to TS or OCD at once, we’re actually testing the whole haystack and asking where we’re more likely to find the needles.”
Using GCTA, the researchers analyzed the same genetic datasets screened in the Molecular Psychiatry reports – almost 1,500 individuals affected with OCD compared with more than 5,500 controls, and nearly TS 1,500 patients compared with more than 5,200 controls. To minimize variations that might result from slight difference in experimental techniques, all genotyping was done by collaborators at the Broad Institute of Harvard and MIT, who generated the data at the same time using the same equipment. Davis was able to analyze the resulting data on a chromosome-by-chromosome basis, along with the frequency of the identified variants and the function of variants associated with each condition.
The results found that the degree of heritability for both disorders captured by GWAS variants is actually quite close to what previously was predicted based on studies of families impacted by the disorders. “This is a crucial point for genetic researchers, as there has been a lot of controversy in human genetics about what is called ‘missing heritability’,” explains Scharf. “For many diseases, definitive genome-wide significant variants account for only a minute fraction of overall heritability, raising questions about the validity of the approach. Our findings demonstrate that the vast majority of genetic susceptibility to TS and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for TS and OCD than for any other complex trait studied to date.”
Nancy Cox, PhD, section chief of Genetic Medicine at the University of Chicago and co-senior author of the PLOS Genetics report, adds, “Despite the fact that we confirm there is shared genetic liability between these two disorders, we also show there are notable differences in the types of genetic variants that contribute to risk. TS appears to derive about 20 percent of genetic susceptibility from rare variants, while OCD appears to derive all of its susceptibility from variants that are quite common, which is something that has not been seen before.”
In terms of the potential impact of the risk-associated variants, about half the risk for both disorders appears to be accounted for by variants already known to influence the expression of genes in the brain. Further investigation of those findings could lead to identification of the affected genes and how the expression changes contribute to the development of TS and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could identify the biologic pathways disrupted in the disorder, potentially leading to new therapeutic approaches.
(Source: medicalxpress.com)
New biological links between sleep deprivation and the immune system discovered
Population-level studies have indicated that insufficient sleep increases the risk of cardiovascular diseases and type 2 diabetes. These diseases are known to be linked to inflammatory responses in the body.
University of Helsinki researchers have now shown what kinds of biological mechanisms related to sleep loss affect the immune system and trigger an inflammatory response. They identified the genes which are most susceptible to sleep deprivation and examined whether these genes are involved in the regulation of the immune system. The study was published in the journal PLOS ONE on October 23, 2013.
Conducted at the sleep laboratory of the Finnish Institute of Occupational Health, the study restricted the amount of sleep of a group of healthy young men to four hours per night for five days, imitating the schedule of a normal working week. Blood samples were taken before and after the sleep deprivation test. White blood cells were isolated from the samples, and the expression of all genes at the time of the sampling was examined using microarrays. The results were compared with samples from healthy men of comparable age who had been sleeping eight hours per night for the week.
"We compared the gene expression before and after the sleep deprivation period, and focused on the genes whose behaviour was most strongly altered," explains researcher Vilma Aho. "The expression of many genes and gene pathways related to the functions of the immune system was increased during the sleep deprivation. There was an increase in activity of B cells which are responsible for producing antigens that contribute to the body’s defensive reactions, but also to allergic reactions and asthma. This may explain the previous observations of increased asthmatic symptoms in a state of sleep deprivation."
The amount of certain interleukins, or signalling molecules which promote inflammation, increased, as did the amount of associated receptors such as Toll-like receptors (TLR). On the gene level, this was apparent in the higher-than-normal expression of the TLR4 gene after sleep loss. CRP level was also elevated, indicating inflammation.
The researchers also wanted to examine the impact that long-term sleep deprivation could have on the immune system. For this follow-up study, they used material from the national FINRISKI health survey. Participants in this population study underwent blood tests but also answered questions about their health, for example whether they were getting enough sleep.
The researchers compared participants who believed they were sleeping sufficiently with those who felt that they were not sleeping enough. Some of the gene-level changes observed in the experimental working week sleep restriction study were repeated in the population sample. These results may help explain the connection between shorter sleep and the development of inflammatory diseases, such as cardiovascular disease and diabetes, which has been established in epidemiological studies.
"These results corroborate the idea that sleep does not only impact brain function, but also interacts with our immune system and metabolism. Sleep loss causes changes to the system that regulates our immune defence. Some of these changes appear to be long-term, and may contribute to the development of diseases that have been linked to sleep deprivation in epidemiological research,” Aho states.
Study points to possible treatment for brain disorders
Clemson University scientists are working to determine how neurons are generated, which is vital to providing treatment for neurological disorders like Tuberous Sclerosis Complex (TSC).
TSC is a rare genetic disease that causes the growth of tumors in the brain and other vital organs and may indicate such disorders as autism, epilepsy and cognitive impairment that may arise from the abnormal generation of neurons.
“Current medicine is directed at inhibiting the mammalian target of rapamycin (mTOR), a common feature within these tumors that have abnormally high activity,” said David M. Feliciano, assistant professor of biological sciences. “However, current treatments have severe side effects, likely due to mTOR’s many functions and playing an important role in cell survival, growth and migration.”
Feliciano and colleagues published their findings in journal Cell Reports.
“Neural stem cells generate the primary communicating cells of the brain called neurons through the process of neurogenesis, yet how this is orchestrated is unknown,” said Feliciano.
The stem cells lie at the core of brain development and repair, and alterations in the cells’ self-renewal and differentiation can have major consequences for brain function at any stage of life, according to researchers.
To better understand the process of neurogenesis, the researchers used a genetic approach known as neonatal electroporation to deliver pieces of DNA into neural stem cells in young mice, which allowed them to express and control specific components of the mTOR pathway.
The researchers found that when they increase activity of the mTOR pathway, neural stem cells make neurons at the expense of making more stem cells. They also found that this phenomenon is linked to a specific mTOR target known as 4E-BP2, which regulates the production of proteins.
Ultimately, this study points to a possible new treatment, 4E-BP2, for neurodevelopmental disorders like TSC and may have fewer side effects.
Future experiments are aimed at identifying which proteins are synthesized due to this pathway in neurological disorders.