Research Roundup: Heart Disease Mutations, Depression and Huntington’s and More
Combination of 3 Mutations Linked to Congenital Heart Disease
Researchers with the Gladstone Institutes and University of California, San Francisco (UCSF) have identified three genetic variations within a family that combined cause heart disease in several siblings at a very young age. The researchers first encountered the family when Deepak Srivastava, a cardiologist at UCSF Benioff Children’s Hospitals and president of Gladstone, treated a two-month-old child with left ventricular noncompaction. In this disease, the cells in the left ventricle don’t mature completely and don’t contract well, which leads to heart failure. She had two siblings with the same condition. The research was published in the journal Science.
“Given the severity of the disease in the children and the fact that one of the parents had an asymptomatic form, we suspected that the condition in the children was caused by a combination of the mother and the father’s genes,” stated Srivastava, senior author of the study.
The research team sequenced the family’s genome and found the father had mutations in MKL2 and MYH7, which increased his risk for heart disease. All three children inherited both these mutations from their father, but a third mutation from the mother, in one copy of the NKX2-5 gene, appears to have increased the problems caused by the father’s genes, which created a more severe form of the disease in the children.
Specific Enzyme Linked to Depression Symptoms in Huntington’s Disease
Approximately 40% of patients with Huntington’s disease show signs of depression, even in the early stages. Huntington’s disease is a fatal genetic disorder that results in progressive deterioration of nerve cells in the brain. Researchers at the University of Barcelona have identified an enzyme, Cdk5 kinase, that appears to be linked to the depressive-like symptoms. They published their research in the journal Biological Psychiatry.
The study showed that in murine models of the disease, Cdk5 had higher activity in two parts of the brain, the nucleus accumbens and the prefrontal cortex, both associated with anxiety and depression processes. The researchers wanted to determine if a decrease in the function of Cdk5 kinase would have therapeutic benefits in the treatment of depression in Huntington’s patients. They found that hyperfunction of Cdk5 kinase changes the signaling pathway of DARPP-32/beta-adducin in the nucleus accumbens brain region. But these pathways are different than those found in typical major depression, which probably explains why conventional anti-depressants don’t do much to alleviate depression symptoms in Huntington’s patients.
“One of the current objectives,” stated Silvia Gines, study lead, is to analyze whether this strategy is also valid once the symptoms come out, and then, see for how long the beneficial effects last. We want to analyze whether preventing the appearance of depressive symptoms has an effect on the appearance of cognitive disorders, either because the latter are lighter, slow or not appearing at all.”
Mapping Epigenetic Causes of Disease
In the last twenty years or so, researchers have learned much more about epigenetics—how genes are switched on and off based on various factors. Scientists with the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital identified a specific section of the genome that they’re calling a “treasure map” to epigenetic regulation. They published their research in the journal Genome Biology.
The team focused on a specific, stable type of epigenetic regulation known as DNA methylation, which means the addition of methyl groups to the DNA molecules. They profiled DNA methylation across the genome in thyroid, heart and brain tissues from each of 10 cadavers. They mapped out almost 10,000 regions, called correlated regions of systemic interindividual variation (CoRSIVs), which were previously unknown areas of molecular individuality.
“Recent studies are already showing that methylation at these regions is associated with a range of human diseases including obesity, cancer, autism, Alzheimer’s disease and cleft palate,” stated Cristian Coarfa, associate professor of molecular and cell biology at Baylor and co-leader of the project.
Antihypertensive Drug May Decrease Dementia Risk
Researchers with the University of Leipzig published a study evaluating clinical practice data to estimate the possibility of drug prescriptions’ effects on delaying or decreasing the development of dementia. They published their research in the Journal of Alzheimer’s Disease.
The study utilized data from the Disease Analyzer database (IQVIA), which collects drug prescriptions, diagnoses, and basic medical and demographic data. The study includes information about documented blood pressure readings and initial diagnoses of all-cause dementia in 739 general medical practices in Germany between January 2013 and December 2017. The primary outcome was that the use of antihypertension medications, including diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers, showed a decreased incidence of dementia.
“Antihypertensive therapy alone cannot guarantee that dementia will never occur,” noted corresponding author Karel Kostev, from the Epidemiology Department of IQVIA (Germany). “However, these findings highlight the importance of the prescription of antihypertensive drugs in the context of preventing hypertension-associated cognitive decline.”
Using Bioinks to 3D Print Therapeutics
3D printing is a way of “printing” three-dimensional objects from a computer file, often using carbon fiber as a source material. In bioprinting, a variety of biological substrates are used. The idea is the possibility of designing and printing functional tissues or even organs. Although it sounds like science fiction, quite a bit of headway has been made in it, but one of the major challenges is control of cellular functions. Researchers with Texas A&M University formulated a bioink made up of 2D mineral nanoparticles that might be used to sequester and 3D print therapeutics. They published their work in the journal Advanced Healthcare Materials.
They essentially invented a new class of hydrogel bioinks loaded with therapeutic proteins. It is made from an inert polymer, polyethylene glycol (PEG), and doesn’t stimulate the immune system. Usually the HPEG polymer doesn’t print well because of low viscosity, but the researcher combined PEG polymers with nanoparticles, which created the hydrogels that support cell growth and may have enhanced printability.
“This formulation using nanoclay sequesters the therapeutic of interest for increased cell activity and proliferation,” stated Charles W. Peak, senior author of the study. “In addition, the prolonged delivery of the bioactive therapeutic could improve cell migration within 3D printed scaffolds and can help in rapid vascularization of scaffolds.”
The Microbiome Produces an Antibiotic
The microbiome is the trillions of bacteria, viruses and fungi that live in the human body. Increasingly they have been found to be involved in numerous disease states—not just the obvious ones—and are involved in cell signaling throughout the body. Researchers from the Universities of Turbingen and Gottingen and the German Center for Infection Research, evaluated a new class of antibiotics produced by the microbiome. They published their research in the journal Angewandte Chemie.
The antibiotic was originally discovered in 2016 by the team and is produced by the microbiome. It has been called lugdunin, after the Staphylococcus lugdunensis bacteria that produced it. It resides in the mucosa of the human nose. Lugdunin’s chemical structure is unusual and is a potential new class of antibiotics. It appears to be effective against methicillin-resistant Staphylococcus aureas (MRSA).
The research group synthesized chemical variants of lugdunin and identified the structural elements that are responsible for its bacteria-killing effect. “Each bacterial cell requires a so-called membrane potential in order to live,” stated lead author Nadine A. Schilling, with the University of Tuebingen. “This means that a pathogen needs different concentrations of electronically charged particles in the cell compared to its outside surroundings. Fibupeptides like lugdunin are able to transport positively charged hydrogen ions across the membrane and consequently dissipate this membrane potential, resulting in a kind of energy standstill.” As a result, the bacteria dies.
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