Rogue mouse brain cells in red. CREDIT Case Western Reserve University
A team led by scientists at the Case Western Reserve University School of Medicine has identified a new therapeutic approach for combating neurodegenerative diseases, offering hope of improved treatments for Alzheimer’s disease, Parkinson’s disease, Vanishing White Matter disease and multiple sclerosis, among others.
Neurodegenerative diseases, which affect millions of people worldwide, occur when nerve cells in the brain or nervous system lose function over time and ultimately die, according to the National Institutes of Health. Alzheimer’s disease and Parkinson’s disease are the most common.
The research team’s new study, published online February 20 in the journal Nature Neuroscience, focused on astrocytes—the brain’s most abundant cells, which normally support healthy brain function. Growing evidence indicates astrocytes can switch to a harmful state that increases nerve-cell loss in neurodegenerative diseases.
The researchers created a new cellular technique to test thousands of possible medications for their ability to prevent these rogue astrocytes from forming.
“By harnessing the power of high-throughput drug-screening, we’ve identified a key protein regulator that, when inhibited, can prevent the formation of harmful astrocytes,” said Benjamin Clayton, lead author and National Multiple Sclerosis Society career transition fellow in the laboratory of Paul Tesar at the Case Western Reserve School of Medicine.
They found that blocking the activity of a particular protein, HDAC3, may prevent the development of dangerous astrocytes. The scientists discovered that by administering medications that specifically target HDAC3, they were able to prevent the development of dangerous astrocytes and significantly increase the survival of nerve cells in mouse models.
Tesar, also director of the School of Medicine’s Institute for Glial Sciences, said more research needs to be done before patients might benefit from the promising approach. But, he said, their findings could lead to the creation of novel therapies that disarm harmful astrocytes and support neuroprotection—perhaps improving the lives of people with neurodegenerative illnesses in the future.
“Therapies for neurodegenerative disease typically target the nerve cells directly,” Tesar said, “but here we asked if fixing the damaging effects of astrocytes could provide therapeutic benefit. Our findings redefine the landscape of neurodegenerative disease treatment and open the door to a new era of astrocyte targeting medicines.”
One of the mysteries of immunology is that the function of B cells (green) in the thymus gland was previously unknown. Researchers have now been able to show that the immune cells help to prevent T cells from attacking the body. CREDIT Jan Böttcher, Thomas Korn / TUM
Immune cells must learn not to attack the body itself. A team of researchers from the Technical University of Munich (TUM) and the Ludwig Maximilian University of Munich (LMU) has discovered a previously unknown mechanism behind this: other immune cells, the B cells, contribute to the “training” of the T cells in the thymus gland. If this process fails, autoimmune diseases can develop. The study confirms this for Neuromyelitis optica, a disease similar to Multiple Sclerosis. Other autoimmune diseases may also be linked to the failure of this new mechanism.
The thymus gland functions as a “school for T cells” in children and adolescents. The organ in our chest is where the precursors of those T cells that would later attack the body’s own cells are discarded. Epithelial cells in the thymus present many molecules that occur in the body to the future T cells. A self-destruction program is triggered if any of them reacts to one of these molecules. T cells that attack the body’s own molecules remaining intact and multiplying, on the other hand, can cause autoimmune diseases.
New mechanism discovered
In Nature, the team led by Thomas Korn, Professor of Experimental Neuroimmunology at TUM and a Principal Investigator in the SyNergy Cluster of Excellence, and Ludger Klein, Professor of Immunology at LMU’s Biomedical Center (BMC), describe another previously unknown mechanism behind this.
In addition to the precursors of T cells, the thymus gland also contains other immune cells, the B cells. They develop in the bone marrow but migrate to the thymus in early childhood. “The function of B cells in the thymus gland has been a mystery that has puzzled immunologists for many years,” says Thomas Korn. The researchers have now been able to show for the first time that B cells play an active role in teaching T cells which targets not to attack.
MS-like disease due to malfunction in tolerance formation
Neuromyelitis optica is an autoimmune disease similar to multiple sclerosis (MS). While it is not yet known which molecules are attacked in MS, it is well-established that T cells respond to the protein AQP4 in neuromyelitis optica. AQP4 is most prominently expressed in cells of the nervous tissue, which then becomes the target of the autoimmune reaction. Frequently, the optic nerve is affected.
The researchers were able to show that in the thymus gland of humans and mice not only the epithelial cells but also B cells express and present AQP4 to the T cell precursors. If the B cells were prevented from doing so in animal experiments, AQP4-reactive T cell precursors were not eliminated and the autoimmune disease developed. This was also the case when the epithelial cells still presented the molecule. The team concludes from this that B cells in the thymus are a necessary condition for immune tolerance regarding AQP4.
Protection against subsequent interactions between T cells and B cells
“We suspect that this previously unknown process has evolved particularly to prevent dangerous interactions between autoreactive T and B cells in the lymph nodes and spleen, the so-called peripheral immune compartment,” says Ludger Klein. Once the immune system is developed, B and T cells can communicate and thus trigger highly effective immune reactions. This is useful when it comes to fighting pathogens quickly. On occasion, however, B cells may accidentally present the body’s own proteins, such as AQP4. If the T cells that react to AQP4 had not been sorted out in the thymus, this could lead to a sudden and violent large-scale attack on the body.
Possible cause of other immune disorders
“We assume that problems with the training of T cells by the B cells in the thymus can cause other autoimmune diseases as well,” says Thomas Korn. “After all, the B cells in the thymus present a whole range of the body’s own proteins. The corresponding interactions must be investigated in further studies.”
According to the researchers, likely suspects include antiphospholipid syndrome (APS) and certain forms of cerebral amyloid angiopathy. “Looking further into the future, this interaction in the thymus might be exploited to treat existing autoimmune diseases in a very targeted manner,” says Thomas Korn.
Improved MRI scans of the myelin sheaths in the brain should allow multiple sclerosis to be detected early. ETH Zurich
Multiple sclerosis (MS) is a neurological disease that usually leads to permanent disabilities. It affects around 2.9 million people worldwide and around 15,000 in Switzerland alone. One key feature of the disease is that it causes the patient’s immune system to attack and destroy the myelin sheaths in the central nervous system. These protective sheaths insulate the nerve fibres like the plastic coating around a copper wire. Myelin sheaths ensure electrical impulses travel quickly and efficiently from nerve to nerve cells. If they are damaged or become thinner, this can lead to irreversible visual, speech and coordination disorders.
So far, however, it hasn’t been possible to visualise the myelin sheaths well enough to use this information for the diagnosis and monitoring of MS.* Now researchers at ETH Zurich and the University of Zurich, led by Markus Weiner and Emily Baadsvik from the Institute for Biomedical Engineering, have developed a new magnetic resonance imaging (MRI) procedure that maps the condition of the myelin sheaths more accurately than was previously possible. The researchers successfully tested the procedure on healthy people for the first time.
In the future, the MRI system, with its special head scanner, could help doctors to recognise MS at an early stage and better monitor the progression of the disease. The technology could also facilitate the development of new drugs for MS. But it doesn’t end there: the new MRI method could also be used by researchers to visualise better other solid tissue types such as connective tissue, tendons and ligaments.
Quantitative myelin maps
Conventional MRI devices capture only inaccurate, indirect images of the myelin sheaths. That’s because most of these devices work by reacting to water molecules in the body that radio waves have stimulated in a strong magnetic field. But the myelin sheaths, which wrap around the nerve fibres in several layers, consist mainly of fatty tissue and proteins. That said, there is some water – known as myelin water – trapped between these layers. Standard MRIs build their images primarily using the signals of the hydrogen atoms in this myelin water, rather than imaging the myelin sheaths directly.
The ETH researchers’ new MRI method solves this problem and measures the myelin content directly. It puts numerical values on MRI images of the brain to show how much myelin is present in a particular area compared to other areas of the image. A number 8, for instance, means that the myelin content at this point is only 8 percent of a maximum value of 100, which indicates a significant thinning of the myelin sheaths. Essentially, the darker the area and the smaller the number in the image, the more the myelin sheaths have been reduced. This information ought to enable doctors to better assess the severity and progression of MS.
Measuring signals within millionths of a second
However, it is difficult to image the myelin sheaths directly. That’s because the signals that the MRI triggers in the tissue are very short-lived; the signals that emanate from the myelin water last much longer. “Put simply, the hydrogen atoms in myelin tissue move less freely than those in myelin water. That means they generate much briefer signals, which disappear again after a few microseconds,” Weiger says, adding: “And bearing in mind a microsecond is a millionth of a second, that’s a very short time indeed.” A conventional MRI scanner can’t capture these fleeting signals because it doesn’t take the measurements fast enough.
To solve this problem, the researchers used a specially customised MRI head scanner that they have developed over the past ten years together with the companies Philips and Futura. This scanner is characterised by a particularly strong gradient in the magnetic field. “The greater the change in magnetic field strength generated by the three scanner coils, the faster information about the position of hydrogen atoms can be recorded,” Baadsvik says.
Generating such a strong gradient calls for a strong current and a sophisticated design. As the researchers scan only the head, the magnetic field is more contained and concentrated than with conventional devices. In addition, the system can quickly switch from transmitting radio waves to receiving signals; the researchers and their industry partners have developed a special circuit for this purpose.
The researchers have already successfully tested their MRI procedure on tissue samples from MS patients and on two healthy individuals. Next, they want to test it on MS patients themselves. Whether the new MRI head scanner will make its way into hospitals in the future now depends on the medical industry. “We’ve shown that our process works,” Weiger says. “Now it’s up to industry partners to implement it and bring it to market.
An international study has used a computational biology tool that, by analysing a multitude of biological data from multiple sclerosis patients ranging from genetic information to the whole organism, reveals the relationship between elements of different.
International research led by the Department of Medicine and Life Sciences (MELIS) at Pompeu Fabra University, in collaboration with Hospital del Mar, Hospital Clínic, Charité – Medical University of Berlin, and the universities of Oslo and Genoa, has developed a computational biology tool, based on multi-level network analysis, to achieve an integrated vision of multiple sclerosis. This tool could be used to study other complex diseases, such as types of dementia.
Multiple sclerosis is an autoimmune disease of unknown cause that occurs when the immune system attacks the brain and spinal cord. It is a complex disease that is not always easy to diagnose and covers a wide range of biological scales, from genes and proteins to cells and tissues, passing through the entire organism.
Symptoms of multiple sclerosis vary among patients, but the most common range from vision problems, asthenia, and difficulty walking and keeping balance to numbness or weakness in the arms and legs. All of them can appear and disappear or last over time.
The study published today in Plos Computational Biology has conducted a multi-level network analysis of multiomic data (genomic, phosphoproteomic and cytomic), brain and retinal images and clinical data of 328 patients with multiple sclerosis and 90 healthy subjects. It is one of the first studies to date that simultaneously analyses data from very different scales, covering everything from genes to the whole organism. Thus, the new tool allows us to understand the complexity of chronic diseases.
“In this study, we have analysed five levels at once: genes, proteins, cells, parts of the brain and behaviour. The proximity of the elements of each level in each person has determined the connection between the elements within each level and between levels and, through Boolean dynamics, considering each element as being active or inactive and the introduction of disturbances in the system, we have made the elements of the network oscillate. Thus, we have managed to identify which elements of the different levels are related at the biological level”, says JordiGarcia-Ojalvo, professor of Systems Biology and director of the Dynamical Systems Biology Laboratory at the UPF Department of Medicine and Life Sciences.
“In complex diseases, as in society, many things happen at once, and they do so on multiple scales and over time. So, for human beings, researchers and physicians, it is hard to visualize it if it is not by using these types of tools that allow us to discern and identify the related elements”, says Pablo Villoslada, an associate professor at the UPF Department of Medicine and Life Sciences, director of the Neurosciences programme of the Hospital del Mar Research Institute and head of the Neurology Service at Hospital del Mar, who co-led the study together with Garcia-Ojalvo.
Thanks to the enormous capacity of networks to simplify complex data, they have managed to reveal the correlation between the protein MK03, previously associated with multiple sclerosis, with the total count of T cells, immune system cells that help fight infections, the thickness of the layer of retinal nerve fibres and the timed gait test, which measures the time it takes a patient to walk 7.5 metres as quickly as possible.
Although the size of the study has not allowed validating the use of this correlation as a biomarker to diagnose and possibly treat multiple sclerosis, it has allowed an integrated view of this complex system and revealed the relationship between four biological scales: proteins, cells, tissues and behaviour.
“In complex diseases it is very difficult to have genetic biomarkers. They are often determined by multiple genes and there is a lot of “background noise”. And here we are studying sets of genes, proteins, and phenotypes, and if they are related to each other, we have an indication of the existence of the disease”, Garcia-Ojalvo adds.
“With multiple sclerosis we have to build a puzzle whose aspect we can more or less intuit. We are not totally in the dark, which is why we use systems biology, which informs us of the relevant relationships between the elements so that the puzzle is coherent, fits and we learn. And once we know how the disease works, we can find out how to deal with it”, Villoslada concludes.
This tool based on the relationship between basic biology and applied medicine could be applied to the study of other complex diseases such as Alzheimer’s and other types of dementia.
omewhere between 24 and 50 million Americans have an autoimmune disease, a condition in which the immune system attacks our own tissues. As many as 4 out of 5 of those people are women.
Stanford Medicine scientists and their colleagues have traced this disparity to the most fundamental feature differentiating biological female mammals from males, possibly paving the way for a better way to predict autoimmune disorders before they develop.
“As a practising physician, I see a lot of lupus and scleroderma patients because those autoimmune disorders manifest in the skin,” said Howard Chang, MD, PhD, dermatology professor and genetics professor and a Howard Hughes Medical Institute investigator. “The great majority of these patients are women.”
Chang, the Virginia and D.K. Ludwig Professor in Cancer Research and director of the RNA Medicine Program, is the senior author of the study, to be published Feb. 1 in Cell. Basic life research scientist Diana Dou, PhD, is its lead author.
The silence of the second X
Women have too much of a good thing: It’s called the X chromosome.
Throughout the mammalian kingdom, biological sex is determined by the presence of two X chromosomes in every female cell. Male cells pack just one X chromosome, paired with a much shorter one designated the Y chromosome.
The stubby Y chromosome contains only a handful of active genes. It’s quite possible to live a full life without a Y chromosome. In fact, more than half of the people on Earth — women — lack Y chromosomes and do just fine. But no mammalian male or female cell can survive without at least one copy of the X chromosome, which holds many hundreds of active protein-specifying genes.
Still, having two X chromosomes risks the production, in every female cell, of twice the amount of the myriad proteins specified by the X but not the Y chromosome. Such massive overproduction of so many proteins would be lethal.
Nature has devised a clever, if complicated, workaround called X-chromosome inactivation. Early in embryogenesis, each cell in the nascent female mammal decides to shut down the activity of one or the other of its two X chromosomes. Once that decision is made, it’s handed down to these cells’ progeny in the developing fetus. That way, the same amount of each X-chromosome-specified protein is produced in a female cell as in a male cell.
As the researchers discovered, X-chromosome inactivation can lead to autoimmune disorders, but other factors can also cause these disorders — which is why men sometimes develop them.
The great equalizer
X-chromosome inactivation is achieved courtesy of a molecule called Xist. The gene for Xist is present on all X chromosomes, including the single one male cells have. But Xist itself is produced only when the X chromosome that its gene resides on is one of a matched XX pair — and is produced and deployed on only one pair member.
Xist consists of RNA, a substance best known for being a simple-minded messenger that shuttles genes’ instructions for making proteins to the intracellular machines that make them. Yet RNA can do a whole lot more than schlep genetic information. There are as many different kinds of so-called long noncoding RNA (lncRNA) molecules — lengthy RNA stretches that don’t carry instructions for making proteins — as there are of the protein-encoding RNA variety. These lncRNA molecules can park themselves on stretches of chromosomes and change the likelihood that the cellular machinery charged with reading the genes in those locations will do so.
Xist, a type of lncRNA, is much longer than most. Xist coats long sections of one of a female mammalian cell’s two X chromosomes — but always just one — cutting that chromosome’s output to zero or close to it. The other X chromosome, left undisturbed, pumps out just enough RNA-encoded instructions to keep the cell humming.
But Xist’s nestling into the extra X chromosome generates odd combinations of lncRNA, proteins that bind to it, other proteins that bind to those proteins, and DNA some of those proteins cling to. These complexes can trigger a strong immune response, Chang and his colleagues have learned.
In 2015, Chang’s group identified close to 100 proteins that either bound to Xist or that bound to those proteins, collectively enabling this molecule to lay anchor along gene-specifying regions of the X chromosome.
Inspecting this Xist “parts list,” Chang realized that many of Xist’s collaborator proteins were known to be associated with autoimmune disorders. Might the RNA-protein-DNA complexes generated in the course of X-chromosome inactivation be triggering the notoriously high rate of autoimmunity in women compared with men? That question was the impetus for the new study.
What if males made Xist?
To eliminate possible competing causes such as female hormonal action or aberrant protein production by the supposedly silenced second X chromosome, the researchers tossed the Xist ball into the male court. They sewed the gene for Xist into the genomes of two different strains of male lab mice. One strain is quite susceptible to autoimmune symptoms mimicking lupus, with females more susceptible than males. The other is resistant to it.
The inserted Xist gene had been modified in two ways. It could be turned on or off by chemical means, pumping out Xist only when the scientists wanted it to. The Xist gene was also tweaked slightly so that its RNA product would no longer silence the genes of the male mouse’s chromosome into which it was stitched.
Merely inserting that modified Xist gene had no noticeable effect on the mice. But the Xist produced from the inserted gene, once that gene was activated, still formed characteristic complexes with almost all the proteins found earlier to be collaborating closely with Xist.
Now, the scientists could ask: Is a bioengineered male mouse that’s been coaxed to produce Xist more prone to autoimmunity than a normal male mouse, which never produces it, or than a male in whom the gene for Xist has been inserted but not activated?
By injecting an irritant known to induce a lupus-like autoimmune condition in the susceptible mouse strain, the investigators could compare its effect on males who made Xist with its effect on normal males, who made none.
In these susceptible mice, males in which the Xist gene was activated developed lupus-like autoimmunity at a rate approaching that of females — and considerably more so than non-bioengineered males.
The absence of autoimmunity in some female or Xist-activated male mice in the susceptible strain showed that not just activation of Xist but also some kind of tissue-damaging stress (caused, in this case, by injection of the irritant) is required to get the autoimmunity ball rolling.
In the autoimmune-resistant strain, activating Xist in bioengineered male mice wasn’t enough to induce autoimmunity — as might be predicted by the fact that in this strain even females seldom develop autoimmunity. That suggests that not only Xist activation but also an appropriate genetic background is necessary for autoimmunity to develop.
These constraints on autoimmunity are fortunate, because if there were none all women might be more susceptible to develop immunity, Chang noted.
Toward a better autoimmunity-screening panel
An early step in the development of autoimmunity is the appearance of autoantibodies: antibodies targeting one’s own tissues or cell products. Autoantibodies to the contents of cell nuclei are called anti-nuclear antibodies. Close examination of blood samples from about 100 patients with autoimmunity showed the presence of autoantibodies to many of the complexes associated with Xist. Some of these autoantibodies were specific to one or another autoimmune disorder, indicating their potential utility in identifying particular emergent autoimmune disorders before symptoms develop. Autoantibodies to still other Xist-associated proteins spanned several disorders, designating them as possible common markers of autoimmunity.
“Every cell in a woman’s body produces Xist,” Chang said. “But for several decades, we’ve used a male cell line as the standard of reference. That male cell line produced no Xist and no Xist/protein/DNA complexes, nor have other cells used since for the test. So, all of a female patient’s anti-Xist-complex antibodies — a huge source of women’s autoimmune susceptibility — go unseen.”
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