In healthy individuals, the Zika virus causes flu-like symptoms. If a pregnant woman becomes infected, the unborn child can suffer from severe brain abnormalities as a result of mechanisms that have not yet been explained. A study by the Technical University of Munich (TUM) and the Max Planck Institute of Biochemistry (MPI-B) shows that Zika virus proteins bind to cellular proteins that are required for neural development.

A few years ago, Zika virus spread across South America, posing a health issue with global impact. A significant number of South American women who came into contact with the virus for the first time at the start of their pregnancy by a mosquito bite subsequently gave birth to children with severe disabilities. The babies suffered from a condition known as microcephaly; they were born with a brain that was too small. This can lead to intellectual disabilities and other serious neurological disorders.

Scientists succeeded in proving that these deformities are caused by Zika virus infections, but so far they have been unable to explain why. Andreas Pichlmair, Chair for Viral Immunopathology at TUM and his team from the TUM Institute of Virology and MPI-B have examined how Zika virus influences human brain cells. They identified the virus proteins with the potential to affect neuronal development in the developing brain.

 “Zika virus is closely related to the Hepatitis C virus and certain tropical diseases such as Dengue and West Nile virus. It is, however, the only virus that causes brain damage in newborns,” explains Pichlmair, who headed the recent study.

The researchers discovered that the virus uses certain cellular proteins to replicate its own genome. These molecules are also important neurological factors in the process of a stem cell developing into a nerve cell. “Our findings suggest that the virus takes these factors away from brain development and uses them to replicate its genome, which prevents the brain from developing properly,” explains the virologist.

When the team headed by Pichlmair removed the factors in the cells, the virus found it much harder to replicate. The researchers were able to demonstrate which virus proteins come in contact with these development factors and cause the brain defects. “Previous studies revealed the virus proteins necessary for the packaging or replication of the viral genome but it was enigmatic to understand how these proteins influence neuronal development. It appears that viral proteins are responsible for causing the serious defects in the unborn – unintentionally we presume,” says Pichlmair.

In their comprehensive proteomics survey, the research team identified cellular proteins that were altered chemically or numerically by the virus or which bound to virus proteins. In this way, they were not only able to illustrate possible reasons for the caused deformities, but also obtained a very clear picture of how the virus reprograms the cell to use it for its own replication. www.tum.de/nc/en/about-tum/news/press-releases/details/34920/

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National Institutes of Health (NIH) scientists have developed an ultrasensitive new test to detect abnormal forms of the protein tau associated with uncommon types of neurodegenerative diseases called tauopathies.  This advance gives them hope of using cerebrospinal fluid, or CSF – an accessible patient sample – to diagnose these and perhaps other, more common neurological diseases, such as Alzheimer’s disease.

Scientists have linked the abnormal deposition of tau in the brain to at least 25 different neurodegenerative diseases. However, to accurately diagnose these diseases, brain tissue often must be analysed after the patient has died. For their study, the researchers used the same test concept they developed when using postmortem brain tissue samples to detect the abnormal tau types associated with Pick disease, Alzheimer’s disease and chronic traumatic encephalopathy (CTE). They adapted the test to use CSF for the detection of abnormal tau of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other less common tauopathies.

They detected abnormal tau in CSF from both living and deceased patients. In one case, the test led to a corrected diagnosis in a patient who had died from CBD, but who was initially diagnosed with PSP. The new test is called 4R RT-QuIC – which stands for 4-repeat tau protein amplified in a real-time, quaking-induced conversion process.

The researchers plan to continue evaluating the clinical performance of 4R RT-QuIC by analysing larger sets of CSF samples. One focus will be to compare test results from tauopathy patients who agree to provide CSF samples both before and after death. The scientists hope this type of evaluation will help them better understand how abnormal tau in CSF evolves during brain disease.

NIHwww.niaid.nih.gov/news-events/nih-scientists-develop-test-uncommon-brain-diseases

Researchers at the University of California, Berkeley, have identified biomarkers – genes and specific brain circuits in mice – associated with a common symptom of depression: lack of motivation.

The finding could guide research to find new ways to diagnose and potentially treat individuals suffering from lack of motivation and bring closer the day of precision medicine for psychiatric disorders like depression.
Depression is the most prevalent mental health disorder in the world, affecting around 9% of the American population each year, and is among the top causes of disability in the workplace. Depression symptoms can differ significantly between patients who have the same depression diagnosis, and the lack of a connection between symptoms and treatments is a main reason that about half of all people with depression fail to respond to medication or other therapies, and that side effects of these medications are common.

“If we had a biomarker for specific symptoms of depression, we simply could do a blood test or image the brain and then identify the appropriate medication for that patient,” said Stephan Lammel, a UC Berkeley assistant professor of molecular and cell biology. “That would be the ideal case, but we are far away from that situation right now.”

Now, for the first time, Lammel and his team have identified genes in a brain region – the lateral habenula – that are strongly turned on, or upregulated, in mice that show reduced motivation as a result of chronic stress. This brain region in mice is not associated with other depression symptoms, including anxiety and anhedonia, the inability to feel pleasure.

“We think that our study not only has the potential to transform how basic scientists study depression in animals, but the combination of anatomical, physiological and molecular biomarkers described could lay the foundation for guiding the development of the next generation of antidepressants that are tailored to specific depression symptoms,” Lammel said.

Lammel is senior author of a paper describing the discovery that appears this week in the journal Neuron. The study was led by first author Ignas Cerniauskas, who is a UC Berkeley graduate student.

Lammel and Cerniauskas work on mouse models of depression that have been a mainstay of basic research on this disorder for the past 60 years. Putting mice under constant stress produces at least three common symptoms of human depression – anxiety, lack of motivation and loss of pleasure – that scientists study to try to understand the disorder in humans.

Until now, however, researchers have sought answers by disregarding the variability of symptoms and instead categorizing all mice as either stressed (“depressed”) or non-stressed (“not depressed”). Cerniauskas and Lammel wanted to try to find changes in the brain that were associated with each specific symptom.

“Unfortunately, depression treatment is currently often based on guesswork. No one treatment works for everyone, and no one has objective data on how to differentiate the enormous variability of depression symptoms and subtypes,” Lammel said. “If we understand specifically how the brain changes in those animals with one certain type of symptom, there may be a way we can specifically reverse these symptoms.”

In response to a recent small clinical study in which doctors electrically stimulated the lateral habenula and found symptom improvement in depressed patients who were resistant to other therapies, Lammel and Cerniauskas decided to investigate that area of the brain. The lateral habenula has received increasing attention in the last few years, in part because it is connected to the dopamine and serotonin systems in the brain, both of which are known to be involved in depression. The most common drugs currently used to treat depression are serotonin reuptake inhibitors (SRIs) such as Zoloft and Prozac.

“After chronic stress, there is an increase in the neural activity of the lateral habenula cells – they fire more, they become overactive – and we found that this overactivity was present only in mice that showed very strong deficits in motivated behaviour, but not in animals that showed anxiety or animals that showed anhedonia,” Lammel said.

His team subsequently identified the specific synapses, cells and circuits in the lateral habenula that are altered by chronic stress in these particular mice, and in collaboration with Csaba Földy and colleagues at the University of Zürich, they found genes that are overexpressed as well.

University of California – Berkley news.berkeley.edu/2019/10/28/new-findings-could-improve-diagnosis-treatment-of-depression/