Researchers cracked the complete genetic code of individual cells in healthy and diseased human lung tissues to find potential new molecular targets for diagnosing and treating the lethal lung disease Idiopathic Pulmonary Fibrosis (IPF).
A team of scientists from Cincinnati Children’s Hospital Medical Center, in collaboration with investigators at Cedars-Sinai Medical Center in Los Angeles, have published their findings.
“This paper identifies a number of novel targets and molecular pathways for IPF, for which there are pharmaceutical approaches,” said Jeffrey Whitsett, MD, lead investigator and co-director of the Perinatal Institute at Cincinnati Children’s. “Airway cells can be obtained by brushing the airway or biopsy, and marker genes can be tested to make a diagnosis or monitor treatment.”
IPF is a common and lethal interstitial lung disease in adults, which means it inflames, scars and reconfigures lung tissues. This causes loss of alveoli, where oxygen and carbon dioxide are normally exchanged. Similar losses of lung function can occur earlier in life, especially in children with diseases caused by mutations in genes critical for surfactant and maintenance of the lung saccules.
Biological processes controlling the formation and function of the lung’s alveolar region require precisely orchestrated interactions between diverse epithelial, stromal and immune cells, according to study authors. Despite many years of extensive laboratory studies of whole tissue samples – trying to identify genetic, cellular and molecular processes that fuel lung ailments like IPF – the precise biology has remained elusive.
To overcome this, Whitsett and colleagues – including first author and bioinformatician Yan Xu, PhD of Cincinnati Children’s – conducted what they believe to be the first-ever single-cell RNA sequence analysis of normal and diseased human lung tissues (all donated with prior informed consent). This provided the authors with a detailed genetic blueprint of all the different epithelial cell types involved in IPF progression and a window to identify aberrant biological processes driving inflammation and fibrosis.
Analysis of normal lung epithelial cells found gene patterns linked to fully formed alveolar type 2 lung cells (AT2 cells), which are important for the production of surfactant, a substance containing a complex of proteins critical to breathing.
Analysis of diseased IPF cells found genetic markers for lung cells that were in indeterminate states of formation, the authors report. IPF cells had lost the normal genetic control systems needed to guide their functions. This study identifies abnormalities in gene expression that can be targeted for therapy of chronic lung diseases like IPF.
Leukemia researchers at Princess Margaret Cancer Centre have developed a 17-gene signature derived from leukemia stem cells that can predict at diagnosis if patients with acute myeloid leukemia (AML) will respond to standard treatment.
The findings could potentially transform patient care in AML by giving clinicians a risk scoring tool that within a day or two of diagnosis can predict individual response and help guide treatment decisions, says co-principal investigator Dr. Jean Wang, Affiliate Scientist at the Princess Margaret, University Health Network (UHN). Dr. Wang is also an assistant professor, Faculty of Medicine, University of Toronto and a hematologist at Toronto General Hospital, UHN.
The new biomarker is named the LSC17 score as it comes from the leukemia stem cells that drive disease and relapse. These dormant stem cells have properties that allow them to resist standard chemotherapy, which is designed to defeat rapidly dividing cancer cells. The persistence of these stem cells is the reason the cancer comes back in patients despite being in remission following treatment. AML is one of the most deadly types of leukemia and the most common type of acute leukemia in adults; it increases in frequency as we age. In Canada, there are more than 1,200 new cases each year. The five-year survival ranges between 20 per cent to 30 per cent and is lower in older people.
The study authors write that using the LSC17 score to single out high-risk patients predicted to have resistant disease “provides clinicians with a rapid and powerful tool to identify AML patients who are less likely to be cured by standard therapy and who could be enrolled in trials evaluating novel upfront or post-remission strategies.”
The researchers identified the LSC17 score by sampling the leukemia stem cell properties of blood or bone marrow samples from 78 AML patients from the cancer centre combined with molecular profiling technology that measures gene expression. Stanley W. K. Ng, a senior PhD candidate in the lab of Dr. Peter Zandstra at the Institute for Biomaterials and Biomedical Engineering, University of Toronto and co-lead author of the paper, used rigorous statistical approaches to develop and test the new “stemness score”, using AML patient data provided by the Princess Margaret leukemia clinic and collaborators in the United States and Europe.
“We identified the minimal set of genes that were most critical for predicting survival in these other groups of AML patients, regardless of where they were treated. With this core 17-gene score, we have shown we can rapidly measure risk in newly diagnosed AML patients,” says Dr. Wang.
In the study, analysis of patient samples demonstrated that high LSC17 scores meant poor outcomes with current standard treatment, even for patients who had undergone allogeneic stem cell transplantation. A low score indicated a patient would respond well to standard treatment and have a long-term remission.
The test to measure the LSC17 score has been adapted to a technology platform called NanoString. As the research team and international collaborators continue to validate the stemness risk score, plans are under way to test the score in a clinical trial at the Princess Margaret, which now has the NanoString system in its molecular diagnostic laboratory.
Princess Margaret Cancer Centre
http://tinyurl.com/jcba4tq
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Researchers at VIB and Ghent University have developed a tool to diagnose Familial Mediterranean Fever (FMF). Particularly common among Mediterranean populations, this genetic disease is characterized by inflammation, fever and severe pain. Because of its complex diagnosis, patients often remain untreated for many years, which can eventually lead to kidney failure. In collaboration with Ghent University Hospital and Antwerp University Hospital, VIB and Ghent University are now planning clinical trials to further validate immunodiagnosis of FMF.
In the Mediterranean basin, including the Middle East and Caucasus, FMF has a prevalence between 1 and 2 per 1,000 inhabitants. FMF is usually diagnosed during childhood, after which a daily, lifelong treatment is necessary. However, accurate diagnosis is complicated by a number of factors: other auto-inflammatory diseases show similar symptoms, the clinical picture is often incomplete in young children, atypical signs may occur, and a suggestive family history is sometimes lacking. Wrong or late diagnosis often even leads to unnecessary surgery and, ultimately, kidney failure.
The lab of professor Mohamed Lamkanfi (VIB-Ghent University) developed an alternative for today’s inadequate diagnosis, efficiently segregating FMF patients from people suffering from other auto-inflammatory diseases and healthy individuals. The tool detects changes in the body’s immune reaction to pyrin, a protein that is usually mutated in FMF. Following successful tests on mice, the tool has been validated in 13 patients in collaboration with physicians from Belgium and Italy.
Prof. Mohamed Lamkanfi (VIB-Ghent University): “As next steps, we are setting up clinical trials in Belgium for which we are actively seeking volunteers – both FMF patients and people suffering from related inflammatory disorders. These trials are funded by, among other parties, the European Research Council and FWO (Research Foundation – Flanders). In addition, labs from the Netherlands and Italy have already expressed interest. We are also exploring possible collaborations with industrial partners in order to make our method available as a diagnostic kit.”
VIB
http://tinyurl.com/zpa6s88
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Chemistry researchers develop a simple diagnostic test that can identify the level of cocaine in a person’s urine or oral fluid. The new test offers a low cost, quick method that could be used for testing at the roadside, in the workplace or in prisons
Current commercially available portable testing kits can give false positive results and cannot tell how much cocaine a person has ingested
For the first time, the researchers have been able to prove that it is possible to confidently detect levels of cocaine and their metabolites using a compact ‘mass spectrometer’ (a chemical-based analytical technique). The test uses chromatography to separate cocaine from other compounds and can not only detect the presence of cocaine but also give quantitative data about the amount of cocaine a person has ingested.
The test was found to offer a level of sensitivity below the cut-off level normally used for oral fluid drug testing, meaning that it can detect even low levels of cocaine in a person’s urine or oral fluid. The technique potentially offers an effective solution for scenarios where a rapid test is required. This could include roadside testing by police of motorists, and also drug testing in the workplace and in prisons.
While there are a number of portable tests for cocaine commercially available, these are mainly based on antibody reagents, which cannot offer quantitative data and – since the cocaine antibody can bind to something that is not cocaine – can give false positive results.
The research paper’s lead author, Mahado Ismail of the University of Surrey, explained, “Surface mass spectrometry is used in a wide range of disciplines to obtain chemical information from the surface of a sample. However until now it has not been possible to translate this method to low cost, portable testing.
“This new method, which extracts analytes from a surface and separates them using chromatography, has been shown to provide a sensitive, accurate result. Our next step will be to test the efficacy of the system for monitoring other drugs of abuse, while we are also looking for follow-on funding to further develop the test.”
University of Surrey
http://tinyurl.com/z65q5du
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Genetic differences in the FADS1 gene determine the risk for many different diseases. The ability to produce polyunsaturated fats like omega-3 and omega-6 differs between individuals and this affects the risk for disturbed metabolism, inflammatory diseases and several types of cancer.
Scientists at Uppsala University and SciLifeLab in Sweden have clarified this in detail.
“After detailed experiments we now know exactly which mutation in the region that is functional and directly involved in FADS1 regulation,” says Gang Pan at the Department of Immunology, Genetics and Pathology, Uppsala University and one of the authors of the article.
In this new study the scientists show that the gene region which controls FADS1 appeared 6 million years ago and is present in human and chimpanzee but not in other species. Since increased production of omega-3 and omega-6 is favourable to brain development this event may have contributed to human evolution. A mutation happened 300,000 years ago which further increased the capacity of the gene to produce both omega-3 and omega-6 fatty acids. This mutation constituted an evolutionary advantage that has led to the more active variant of FADS1 being the common one in major parts of the world.
In historical times people ate equal amounts of omega-3, coming from fish and vegetables, and omega-6 coming from meat and egg.
“Since we now live longer and have changed our diet radically – modern food in the Western world has drastic excess of omega-6 – what was an advantage in historical times may have turned against us and become an increased risk for many diseases,” says Gang Pan.
The genetic difference at FADS1 affects levels of LDL- and HDL-cholesterol, several other important fats, blood sugar and the metabolic syndrome, as well as how well we respond to treatment to control blood fat. It affects the risk for allergies and inflammatory diseases like rheumatism and inflammatory bowel disease. In addition it influences the risk for colon cancer and other types of cancer, as well as the heart rate.
“Polyunsaturated fats are involved in a surprising number of processes and the hope is that the new knowledge will make it possible to treat some of these diseases in a targeted way,” says Claes Wadelius, Professor of Medical Genetics at Uppsala University/SciLIfeLab, Sweden and the main author of the study.
Uppsala University
http://tinyurl.com/jc8xek6
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Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment.
Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate grade gliomas.
“As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations,” said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center.
According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent.
Knowing the probable survival status of an individual patient may help physicians choose the best treatment.
In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis.
“Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined,” said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.
UT Southwestern Medical Center
http://tinyurl.com/gmpddac
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Investigators at Rush University Medical Center and the Brigham and Women’s Hospital in Boston reported the discovery of a new gene that is associated with susceptibility to a common form of brain pathology called Tau that accumulates in several different conditions, including Alzheimer’s disease, certain forms of dementia and Parkinsonian syndromes as well as chronic traumatic encephalopathy that occurs with repeated head injuries. The manuscript describes the identification and validation of a genetic variant within the protein tyrosine phosphatase receptor-type delta (PTPRD) gene. “Aging leads to the accumulation of many different pathologies in the brain,” said co-principal investigator Dr. David Bennett who directs the Alzheimer Disease Center at Rush. “One of the most common forms of pathology is the neurofibrillary tangle (NFT) that was at the centre of our study,” he said. “The NFT is thought to be more closely related to memory decline than other forms of aging-related pathologies, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer’s disease and other brain diseases.” Using autopsies from 909 individuals participating in studies of aging based at Rush University, the team of investigators assessed the human genome for evidence that a genetic variant could affect NFT. “The variant that we discovered is common: Most people have one or two copies of the version of the gene that is linked to accumulating more pathology as you get older," said lead author Dr. Lori Chibnik of Brigham and Women’s Hospital. "Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanisms.” The reported results offer an important new lead as the field of neurodegeneration searches for robust novel targets for drug development. This is especially true given the recent disappointing results in Alzheimer’s disease trials targeting amyloid, the other major form of pathology related to Alzheimer’s disease. Tau pathology is more closely connected to loss of brain function with advancing age and may be more impactful as a target. The advent of new techniques to measure Tau in the brains of living individuals with positron emission tomography offers a biomarker for therapies targeting Tau. “This study is an important first step," Dr. De Jager, co-principal investigator at Brigham and Women’s Hospital, notes. "However, the result needs further validation, and the mechanism by which the PTPRD gene and the variant that we have discovered contribute to the accumulation of NFT remains elusive. Other studies in mice and flies implicate PTPRD in memory dysfunction and worsening of Tau pathology, suggesting that altering the level of PTPRD activity could be helpful in reducing an individual’s burden of Tau pathology.” Rush University Medical Center www.rush.edu/news/press-releases/new-gene-discovered-associated-tau-pathology
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A person carrying variants of two particular genes could be almost three times more likely to develop multiple sclerosis, according to the latest findings from scientists at The University of Texas Medical Branch at Galveston and Duke University Medical Center. One of these variants is in IL7R, a gene previously associated with MS, and the other in DDX39B, a gene not previously connected to the disease. The discovery could open the way to the development of more accurate tests to identify those at greatest risk of MS, and possibly other autoimmune disorders, the researchers said. A disease in which the body’s own immune system attacks nerve cells in the spinal cord and brain, MS is a major cause of neurological disease in younger adults, from 20 to 50 years of age, and disproportionally affects women. While treatable, there is no cure for MS, which can lead to problems with vision, muscle control, balance, basic body functions, among other symptoms, and could lead to disability. Available treatments have adverse side effects as they focus on slowing the progression of the disease through suppression of the immune system. Thanks to the collaboration between scientists at UTMB, Duke, University of California, Berkeley, and Case Western Reserve University, researchers found that when two particular DNA variants in the DDX39B and IL7R genes are present in a person’s genetic code, their interaction can lead to an over production of a protein, sIL7R. That protein’s interactions with the body’s immune system plays an important, but not completely understood, role in MS. “Our study identifies an interaction with a known MS risk gene to unlock a new MS candidate gene, and in doing so, open up a novel mechanism that is associated with the risk of multiple sclerosis and other autoimmune diseases,” said Simon Gregory, director of Genomics and Epigenetics at the Duke Molecular Physiology Institute at Duke University Medical Center and co-lead author of the paper in Cell. This new information has potentially important applications. “We can use this information at hand to craft tests that could allow earlier and more accurate diagnoses of multiple sclerosis, and uncover new avenues to expand the therapeutic toolkit to fight MS, and perhaps other autoimmune disorders,” said Gaddiel Galarza-Muñoz, first author on the study and postdoctoral fellow at UTMB. It can sometimes take years before an MS patient is properly diagnosed allowing the diseases to progress and resulting in further damage to the nervous system before treatment begins. With more accurate measures of risk, health care providers would be able to screen individuals with family histories of MS or with other suspicious symptoms. It could lead those with certain genotypes to be more vigilant.
University of Texas Medical Branch www.utmb.edu/newsroom/article11473.aspx
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The molecular causes of diseases such as Parkinson’s need to be understood as a first step towards combating them. University of Konstanz chemists working alongside Professor Malte Drescher recently succeeded in analysing what happens when selective mutations of the alpha-synuclein protein occur – a protein that is closely linked to Parkinson’s disease. In a complex series of experiments they examined what the effects were of changing a single amino acid in the protein. The physicochemists were able to prove how this tiny change disturbs the binding of alpha-synuclein to membranes. “We hope that the finding of this selectively defective membrane binding will help us to understand how Parkinson’s develops on a molecular level. Ultimately, this will facilitate the devising of therapeutic strategies,” outlines Julia Cattani, a doctoral student, who played a major role in the success of the research. The human brain contains large quantities of the small alpha-synuclein protein. Its exact biological function is still unknown, yet it is closely linked to Parkinson’s disease; the protein “clumps together” in the nerve cells of Parkinson patients. Alpha-synuclein consists of a chain of 140 amino acids. In rare cases Parkinson’s disease is hereditary; where this occurs one of these 140 components has been replaced. Malte Drescher and his working group in the Department of Chemistry at the University of Konstanz have now found out the influence these selective changes in the protein sequence can have on the behaviour of alpha-synuclein. “We can show that the selective mutations disturb the membrane binding of alpha-synuclein on a local level,” explains Malte Drescher. To find out more about the influence of selective mutations, the Konstanz-based chemists Dr Marta Robotta and Julia Cattani applied tiny magnetic probe molecules to various places on the alpha-synuclein protein. With the help of electron paramagnetic resonance spectroscopy – a procedure similar in method to magnetic resonance imaging (MRI) used in the medical field – the researchers were able to measure the rotation of these nanomagnets. At every residue at which alpha-synuclein binds to a membrane, the rotation slows down. In this way they were able to find out precisely when and where a binding to the membranes takes place – and when it does not. In the case of the exchanged amino acids the physicochemists from Konstanz discovered a disturbance of the membrane binding of alpha-synuclein – an important clue for the molecular context of Parkinson’s disease. “We went to great lengths, performing over 200 spectroscopic experiments, the results of which we compared with our models by means of a specially developed simulation algorithm. The outcome certainly compensated our efforts,” says Julia Cattani. Project leader Malte Drescher believes that alongside the huge commitment of his staff, an important prerequisite for the success of the research was, above all, the environment of the Collaborative Research Centre (SFB) 969, “Chemical and biological principles of cellular proteostasis” which formed the basis for sponsoring the project: “By networking on an interdisciplinary level and discussing with colleagues we managed to solve the many problems we faced,” emphasises Malte Drescher.
University of Konstanz www.uni-konstanz.de/en/university/news-and-media/current-announcements/news/news-in-detail/parkinson-auf-der-spur/
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Researchers from Trinity College Dublin have shown for the first time that Motor Neurone Disease (MND) — also known as Amyotrophic Lateral Sclerosis (ALS) — and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked. By analysing the genetic profiles of almost 13,000 MND cases and over 30,000 schizophrenia cases, the researchers have confirmed that many of the genes that are associated with these two very different conditions are the same. In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia. While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between MND and psychiatric conditions has been shown. Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said: “This study demonstrates the power of genetics in understanding the causes of diseases." "While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.” Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre at Beaumont Hospital Dublin, Orla Hardiman, is the senior author and lead investigator on the project. Professor Hardiman said: “Our work over the years has shown us that MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.” She continued: “So instead of thinking of MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilise the failing brain networks." “The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one. We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock-on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions." The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman. These studies showed that people with MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide. This was first noted as family histories were ascertained from people with MND in the National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013. This led the Trinity group to team up with European collaborators in MND including the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia to see if these epidemiological observations could be due to a genetic overlap between MND and schizophrenia. The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.
Trinity College Dublin www.tcd.ie/news_events/articles/scientists-discover-shared-genetic-origin-for-mnd-and-schizophrenia/7681
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“Marker genes” reveal deadly secrets of Idiopathic Pulmonary Fibrosis
, /in E-News /by 3wmediaStem cell-based test predicts leukemia patients’ response to therapy
, /in E-News /by 3wmediaScientists develop diagnostic tool for Familial Mediterranean Fever
, /in E-News /by 3wmediaNew test for cocaine in urine and oral fluid could lead to rapid, low cost roadside testing
, /in E-News /by 3wmediaSingle gene found connected to many diseases
, /in E-News /by 3wmediaNew biomarker for brain cancer prognosis
, /in E-News /by 3wmediaGene discovered associated with Tau pathology
, /in E-News /by 3wmediaInvestigators at Rush University Medical Center and the Brigham and Women’s Hospital in Boston reported the discovery of a new gene that is associated with susceptibility to a common form of brain pathology called Tau that accumulates in several different conditions, including Alzheimer’s disease, certain forms of dementia and Parkinsonian syndromes as well as chronic traumatic encephalopathy that occurs with repeated head injuries.
The manuscript describes the identification and validation of a genetic variant within the protein tyrosine phosphatase receptor-type delta (PTPRD) gene.
“Aging leads to the accumulation of many different pathologies in the brain,” said co-principal investigator Dr. David Bennett who directs the Alzheimer Disease Center at Rush. “One of the most common forms of pathology is the neurofibrillary tangle (NFT) that was at the centre of our study,” he said. “The NFT is thought to be more closely related to memory decline than other forms of aging-related pathologies, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer’s disease and other brain diseases.”
Using autopsies from 909 individuals participating in studies of aging based at Rush University, the team of investigators assessed the human genome for evidence that a genetic variant could affect NFT.
“The variant that we discovered is common: Most people have one or two copies of the version of the gene that is linked to accumulating more pathology as you get older," said lead author Dr. Lori Chibnik of Brigham and Women’s Hospital. "Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanisms.”
The reported results offer an important new lead as the field of neurodegeneration searches for robust novel targets for drug development. This is especially true given the recent disappointing results in Alzheimer’s disease trials targeting amyloid, the other major form of pathology related to Alzheimer’s disease.
Tau pathology is more closely connected to loss of brain function with advancing age and may be more impactful as a target. The advent of new techniques to measure Tau in the brains of living individuals with positron emission tomography offers a biomarker for therapies targeting Tau.
“This study is an important first step," Dr. De Jager, co-principal investigator at Brigham and Women’s Hospital, notes. "However, the result needs further validation, and the mechanism by which the PTPRD gene and the variant that we have discovered contribute to the accumulation of NFT remains elusive. Other studies in mice and flies implicate PTPRD in memory dysfunction and worsening of Tau pathology, suggesting that altering the level of PTPRD activity could be helpful in reducing an individual’s burden of Tau pathology.”
Rush University Medical Center
www.rush.edu/news/press-releases/new-gene-discovered-associated-tau-pathology
New gene interaction associated with increased MS risk
, /in E-News /by 3wmediaA person carrying variants of two particular genes could be almost three times more likely to develop multiple sclerosis, according to the latest findings from scientists at The University of Texas Medical Branch at Galveston and Duke University Medical Center.
One of these variants is in IL7R, a gene previously associated with MS, and the other in DDX39B, a gene not previously connected to the disease.
The discovery could open the way to the development of more accurate tests to identify those at greatest risk of MS, and possibly other autoimmune disorders, the researchers said.
A disease in which the body’s own immune system attacks nerve cells in the spinal cord and brain, MS is a major cause of neurological disease in younger adults, from 20 to 50 years of age, and disproportionally affects women. While treatable, there is no cure for MS, which can lead to problems with vision, muscle control, balance, basic body functions, among other symptoms, and could lead to disability.
Available treatments have adverse side effects as they focus on slowing the progression of the disease through suppression of the immune system.
Thanks to the collaboration between scientists at UTMB, Duke, University of California, Berkeley, and Case Western Reserve University, researchers found that when two particular DNA variants in the DDX39B and IL7R genes are present in a person’s genetic code, their interaction can lead to an over production of a protein, sIL7R. That protein’s interactions with the body’s immune system plays an important, but not completely understood, role in MS.
“Our study identifies an interaction with a known MS risk gene to unlock a new MS candidate gene, and in doing so, open up a novel mechanism that is associated with the risk of multiple sclerosis and other autoimmune diseases,” said Simon Gregory, director of Genomics and Epigenetics at the Duke Molecular Physiology Institute at Duke University Medical Center and co-lead author of the paper in Cell.
This new information has potentially important applications.
“We can use this information at hand to craft tests that could allow earlier and more accurate diagnoses of multiple sclerosis, and uncover new avenues to expand the therapeutic toolkit to fight MS, and perhaps other autoimmune disorders,” said Gaddiel Galarza-Muñoz, first author on the study and postdoctoral fellow at UTMB.
It can sometimes take years before an MS patient is properly diagnosed allowing the diseases to progress and resulting in further damage to the nervous system before treatment begins.
With more accurate measures of risk, health care providers would be able to screen individuals with family histories of MS or with other suspicious symptoms. It could lead those with certain genotypes to be more vigilant.
University of Texas Medical Branch
www.utmb.edu/newsroom/article11473.aspx
On the trail of Parkinson’s disease
, /in E-News /by 3wmediaThe molecular causes of diseases such as Parkinson’s need to be understood as a first step towards combating them. University of Konstanz chemists working alongside Professor Malte Drescher recently succeeded in analysing what happens when selective mutations of the alpha-synuclein protein occur – a protein that is closely linked to Parkinson’s disease. In a complex series of experiments they examined what the effects were of changing a single amino acid in the protein. The physicochemists were able to prove how this tiny change disturbs the binding of alpha-synuclein to membranes. “We hope that the finding of this selectively defective membrane binding will help us to understand how Parkinson’s develops on a molecular level. Ultimately, this will facilitate the devising of therapeutic strategies,” outlines Julia Cattani, a doctoral student, who played a major role in the success of the research.
The human brain contains large quantities of the small alpha-synuclein protein. Its exact biological function is still unknown, yet it is closely linked to Parkinson’s disease; the protein “clumps together” in the nerve cells of Parkinson patients. Alpha-synuclein consists of a chain of 140 amino acids. In rare cases Parkinson’s disease is hereditary; where this occurs one of these 140 components has been replaced. Malte Drescher and his working group in the Department of Chemistry at the University of Konstanz have now found out the influence these selective changes in the protein sequence can have on the behaviour of alpha-synuclein. “We can show that the selective mutations disturb the membrane binding of alpha-synuclein on a local level,” explains Malte Drescher.
To find out more about the influence of selective mutations, the Konstanz-based chemists Dr Marta Robotta and Julia Cattani applied tiny magnetic probe molecules to various places on the alpha-synuclein protein. With the help of electron paramagnetic resonance spectroscopy – a procedure similar in method to magnetic resonance imaging (MRI) used in the medical field – the researchers were able to measure the rotation of these nanomagnets. At every residue at which alpha-synuclein binds to a membrane, the rotation slows down. In this way they were able to find out precisely when and where a binding to the membranes takes place – and when it does not. In the case of the exchanged amino acids the physicochemists from Konstanz discovered a disturbance of the membrane binding of alpha-synuclein – an important clue for the molecular context of Parkinson’s disease.
“We went to great lengths, performing over 200 spectroscopic experiments, the results of which we compared with our models by means of a specially developed simulation algorithm. The outcome certainly compensated our efforts,” says Julia Cattani. Project leader Malte Drescher believes that alongside the huge commitment of his staff, an important prerequisite for the success of the research was, above all, the environment of the Collaborative Research Centre (SFB) 969, “Chemical and biological principles of cellular proteostasis” which formed the basis for sponsoring the project: “By networking on an interdisciplinary level and discussing with colleagues we managed to solve the many problems we faced,” emphasises Malte Drescher.
University of Konstanz
www.uni-konstanz.de/en/university/news-and-media/current-announcements/news/news-in-detail/parkinson-auf-der-spur/
Shared genetic origin for MND and schizophrenia
, /in E-News /by 3wmediaResearchers from Trinity College Dublin have shown for the first time that Motor Neurone Disease (MND) — also known as Amyotrophic Lateral Sclerosis (ALS) — and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked.
By analysing the genetic profiles of almost 13,000 MND cases and over 30,000 schizophrenia cases, the researchers have confirmed that many of the genes that are associated with these two very different conditions are the same.
In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between MND and psychiatric conditions has been shown.
Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said: “This study demonstrates the power of genetics in understanding the causes of diseases."
"While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.”
Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre at Beaumont Hospital Dublin, Orla Hardiman, is the senior author and lead investigator on the project.
Professor Hardiman said: “Our work over the years has shown us that MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.”
She continued: “So instead of thinking of MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilise the failing brain networks."
“The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one. We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock-on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions."
The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman. These studies showed that people with MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide.
This was first noted as family histories were ascertained from people with MND in the National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013.
This led the Trinity group to team up with European collaborators in MND including the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia to see if these epidemiological observations could be due to a genetic overlap between MND and schizophrenia.
The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.
Trinity College Dublin
www.tcd.ie/news_events/articles/scientists-discover-shared-genetic-origin-for-mnd-and-schizophrenia/7681