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Archive - Sep 1, 2017


Asthma Drug Targeting Beta2-Adrenoreceptor May Be Effective in Reducing Parkinson’s Disease by Turning Down Production of Alpha-Synclein

Lewy bodies - abnormal clumps of alpha-synuclein protein that accumulate in the brain - are a hallmark of Parkinson's disease (PD). Traditional drug development approaches for PD have focused on clearing alpha-synuclein from the brain or on preventing its downstream effects. But researchers from Brigham and Women's Hospital (BWH) in Boston want to prevent alpha-synuclein from accumulating in the first place. To do so, the team searched for drugs that turn down alpha-synuclein production. They then tested the drugs in mice and stem cells and studied the health records of millions of people living in Norway. The results of their efforts, which point to a new drug development path for PD, were published in the September 1, 2017 issue of Science. The article is titled “Beta2-Adrenoreceptor Is a Regulator of the alpha-Synuclein Gene Driving Risk of Parkinson's.” "Our study suggests a potential new pathway to target PD," said corresponding author Clemens Scherzer, MD, a neurologist and principal investigator at the Ann Romney Center for Neurologic Diseases at BWH and Harvard Medical School. The research team screened more 1,100 drugs already approved for treating diseases other than PD, looking for compounds that could be repurposed for lowering alpha-synuclein production in neuronal cells. They narrowed in on promising candidates, members of a class of drugs known as beta2-adrenergic agonists. The team studied the effects of this class of drugs in mice, finding that it could significantly reduce alpha-synuclein levels. Working with collaborators from the University of Bergen in Norway, the team combed through data from the health records of more than 4 million Norwegians, pulling out information on patients who had been taking salbutamol, a beta2-adrenergic agonist commonly used to treat of asthma.

Nischarin Protein Plays Key Role in Energy Metabolism; Inhibition May Prove Useful in Treatment or Prevention of Obesity & Diabetes, According to JBC Article

Research led by Suresh Alahari, PhD, Fred Brazda Professor of Biochemistry and Molecular Biology at LSU Health New Orleans School of Medicine, has demonstrated the potential of a particular protein to treat or prevent metabolic diseases including obesity and diabetes. The findings were published online on August 24, 2017 in the Journal of Biological Chemistry. The open-access article is titled “Nischarin Inhibition Alters Energy Metabolism by Activating AMP-Activated Protein Kinase.” Nischarin is a novel protein discovered by the Alahari lab. The research team demonstrated that it functions as a molecular scaffold that holds and interacts with several protein partners in a number of biological processes. The lab's earlier research found that Nischarin acts as a tumor suppressor that may inhibit the metastasis of breast and other cancers. The current research project, conducted in a knockout mouse model, found that Nischarin interacts with and controls the activity of a gene called AMPK. AMPK regulates metabolic stability. The research team discovered that Nischarin binds to AMPK and inhibits its activity. In Nischarin-deleted mice, the researchers found decreased activation of genes that make glucose. The study showed that Nischarin also interacts with a gene regulating glucose uptake. Blood glucose levels were lower in the knockout mice, with improved glucose and insulin tolerance. As well, the researchers showed that Nischarin mutation inhibits several genes involved in fat metabolism and the accumulation of fat in the liver. The knockout mice displayed increased energy expenditure despite their smaller growth and appetite suppression leading to decreased food intake and weight reduction.

Pathogenic Tick-Borne Virus Uses Host Neurons’ Transportation System to Move Its RNA

Flaviviruses are a significant threat to public health worldwide, and some infected patients develop severe, potentially fatal, neurological diseases. Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, causes encephalic diseases resulting in photophobia, irritability, and sleep disorders. However, little is known about the pathogenic mechanisms and no effective treatment is available at present. A research team at Hokkaido University in Japan has previously showed that, in mouse neurons, genomic RNAs of TBEV are transported from the cell body to dendrites, the neuron's wire-like protrusions. Viral RNAs then reproduce viruses locally in dendrites disturbing normal neuronal activities. In the new study published online on August 28, 2017 in PNAS, the team looked into the transportation mechanism of viral RNAs in neurons, and discovered these RNAs make use of the cell's transportation system, which is normally used to move neuronal RNAs in dendrites. A specific non-coding sequence near the terminus of viral RNAs was found pivotal in interacting with the transportation system. When the sequence was mutated, the infected mouse showed reduced neurological symptoms. In the researchers’ biochemical experiments, viral RNAs could bind to a protein that forms a neuronal granule, which is part of the neuron's transportation system. Furthermore, their data shows that normal transportation of neuronal RNAs becomes affected by viral RNAs as a result of competition to use the transportation network. Associate Professor Kentaro Yoshii, who led the research team, commented "It is unprecedented for a neuropathogenic virus to hijack the neuronal granule system to transport their genomic RNA, which results in severe neurological diseases.

Gut Bacteria That “Talk” to Human Cells May Lead to New Treatments

We have a symbiotic relationship with the trillions of bacteria that live in our bodies—they help us and we help them. It turns out that they may even speak the same language as we do. And new research from The Rockefeller University and the Icahn School of Medicine at Mount Sinai suggests these newly discovered commonalities may open the door to “engineered” gut flora that can have therapeutically beneficial effects on disease. “We call it mimicry,” says Dr. Sean Brady, Director of Rockefeller University’s Laboratory of Genetically Encoded Small Molecules, where the research was conducted. The breakthrough is described in a paper published online on August 30, 2017 in Nature. The article is titled “Commensal bacteria Make GPCR Ligands That Mimic Human Signalling Molecules.” In a double-barreled discovery, Dr. Brady and co-investigator Dr. Louis Cohen found that gut bacteria and human cells, though different in many ways, speak what is basically the same chemical language, based on molecules called ligands. Building on that, they developed a method to genetically engineer the bacteria to produce molecules that have the potential to treat certain disorders by altering human metabolism. In a test of their system on mice, the introduction of modified gut bacteria led to reduced blood glucose levels and other metabolic changes in the animals. The method involves the lock-and-key relationship of ligands, which bind to receptors on the membranes of human cells to produce specific biological effects. In this case, the bacteria-derived molecules are mimicking human ligands that bind to a class of receptors known as GPCRs, for G-protein-coupled receptors. Many of the GPCRs are implicated in metabolic diseases, Dr. Brady says, and are the most common targets of drug therapy.