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July 28th, 2019

Discovery of Alpha-Synclein DNA Repair Function Could Lead to New Treatments for Parkinson's & Other Brain Diseases

A small protein previously associated with cell dysfunction and death in fact serves a critical function in repairing breaks in DNA, according to new research led by scientists at Oregon Health & Science University (OHSU). The discovery, published online on July 29, 2019 in Scientific Reports, marks the first demonstration of the role that alpha-synuclein plays in preventing the death of neurons in brain diseases such as Parkinson's, which affects 1.5 million people in the United States alone. The findings suggest that it may be possible to design new therapies to replace alpha-synuclein's function or boost it in people with Parkinson's disease and other neurodegenerative disorders. Aggregates of alpha-synuclein, known as Lewy bodies, have long been connected to Parkinson's and other forms of dementia. The study published today casts a new light on that process. The open-access article is titled “Alpha-Synuclein Is a DNA Binding Protein That Modulates DNA Repair with Implications for Lewy Body Disorders.” The findings suggest that Lewy bodies are problematic because they pull alpha-synuclein protein out of the nucleus of brain cells. The study, which examined the cells of living mice and postmortem brain tissue in humans, reveals that these proteins perform a crucial function by repairing breaks that occur along the vast strands of DNA present in the nucleus of every cell of the body. Alpha-synuclein's role in DNA repair may be crucial in preventing cell death. This function may be lost in brain diseases such as Parkinson's, leading to the widespread death of neurons. "It may be the loss of that function that's killing that cell," said senior author Vivek Unni, MD, PhD, an Associate Professor of Neurology in the OHSU School of Medicine.

July 28th

Certain Gut Bacteria (Clostridia) Prevent Obesity in Mice; Population of These Bacteria Influenced by Immune System; Possible Clues to Human Obesity

Researchers at University of Utah Health have identified a specific class of bacteria from the gut that prevents mice from becoming obese, suggesting these same microbes may similarly control weight in people. The beneficial bacteria, called Clostridia, are part of the microbiome – collectively, trillions of bacteria and other microorganisms that inhabit the intestine. Published in the July 26, 2019 issue of Science, the study shows that healthy mice have plenty of Clostridia -- a class of 20 to 30 bacteria -- but those mice with an impaired immune system lose these microbes from their gut as they age. Even when fed a healthy diet, the mice inevitably become obese. Giving this class of microbes back to these animals allowed them to stay slim. The Science article is titled “T Cell-Mediated Regulation of the Microbiota Protects Against Obesity.” June Round, PhD, an Associate Professor of Pathology at U of U Health, is the study's co-senior author along with U of U Health Research Assistant Professor W. Zac Stephens, PhD. Charisse Petersen, PhD, a graduate student at the time, led the research. "Now that we've found the minimal bacteria responsible for this slimming effect, we have the potential to really understand what the organisms are doing and whether they have therapeutic value," Dr. Round says. Results from this study are already pointing in that direction. Dr. Petersen and colleagues found that Clostridia prevents weight gain by blocking the intestine's ability to absorb fat. Mice experimentally treated so that Clostridia were the only bacteria living in their gut were leaner with less fat than mice that had no microbiome at all. They also had lower levels of a gene, CD36, that regulates the body's uptake of fatty acids. These insights could lead to a therapeutic approach, Dr.

Bacteria Separated by Billions of Years of Evolution and Employing Different Mechanisms of Photosynthesis Share Common Photosynthetic Sites; Results Suggest New View of Evolution of Photosynthesis

Structures inside rare bacteria are similar to those that power photosynthesis in plants today, suggesting the process is older than assumed. The finding could mean the evolution of photosynthesis needs a rethink, turning traditional ideas on their head. Photosynthesis is the ability to use the Sun's energy to produce sugars via chemical reactions. Plants, algae, and some bacteria today perform “oxygenic” photosynthesis, which splits water into oxygen and hydrogen to power the process, releasing oxygen as a waste product. Some bacteria instead perform “anoxygenic” photosynthesis, a version that uses molecules other than water to power the process and does not release oxygen. Scientists have always assumed that anoxygenic photosynthesis is more “primitive,” and that oxygenic photosynthesis evolved from it. Under this view, anoxygenic photosynthesis emerged about 3.5 billion years ago and oxygenic photosynthesis evolved a billion years later. However, by analysing structures inside an ancient type of bacteria, Imperial College London researchers have suggested that a key step in oxygenic photosynthesis may have already been possible a billion years before commonly thought. The new research was published online on July 24, 2019 in Trends in Plant Science. The article is titled “Evolution of Photochemical Research Centres: More Twists?” Lead author of the study, Dr. Tanai Cardona from the Department of Life Sciences at Imperial, said: "We're beginning to see that much of the established story about the evolution of photosynthesis is not supported by the real data we obtain about the structure and functioning of early bacterial photosynthesis systems." The bacteria they studied, Heliobacterium modesticaldum, is found around hot springs, soils, and waterlogged fields, where it performs anoxygenic photosynthesis.

Researchers Uncover New Evidence for Origin of RNA Splicing Within Human Genes; Strongest Evidence to Date That the Spliceosome Evolved from a Bacterial Group II Intron

Old-school Hollywood editors cut unwanted frames of film and patched in desired frames to make a movie. The human body does something similar--trillions of times per second--through a biochemical editing process called RNA splicing. Rather than cutting film, it edits the messenger RNA that is the blueprint for producing the many proteins found in cells. In their exploration of the evolutionary origins and history of RNA splicing and the human genome, UC San Diego biochemists Navtej Toor, PhD, and Daniel Haack, PhD, combined two-dimensional (2D) images of individual molecules to reconstruct a three-dimensional (3D) picture of a portion of RNA--what the scientists call group II introns. In so doing, they discovered a large-scale molecular movement associated with RNA catalysis that provides evidence for the origin of RNA splicing and its role in the diversity of life on Earth. Their breakthrough research is outlined in the July 25, 2019 issue of Cell. The article is titled “Cryo-EM Structures of a Group II Intron Reverse Splicing into DNA.” "We are trying to understand how the human genome has evolved starting from primitive ancestors. Every human gene has unwanted frames that are non-coding and must be removed before gene expression. This is the process of RNA splicing," stated Dr. Toor, an Associate Professor in the Department of Chemistry and Biochemistry, adding that 15 percent of human diseases are the result of defects in this process.

July 27th

New CRISPR Platform (RESCUE) Expands RNA Editing Capabilities; Enables Cytosine to Uridine Changes; Zhang Team Shows That Technique Can Be Used to Convert APOE4 Alzheimer’s Risk Variant to APOE2 Non-Risk Variant

CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12, and by targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain. McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang (photo), PhD, and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), which they describe in an article published in the July 26, 2019 issue of Science. The article is titled “A Cytosine Deaminase for Programmable Single-Base RNA Editing.” Dr. Zhang and his team, including first co-authors Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, (both now McGovern Fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine -- thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang's team that changes adenine bases into inosine in RNA. RESCUE significantly expands the landscape that CRISPR tools can target RNA coding for modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.

Scientists Find New Cause of Cellular Aging--Cells Stop Making Nucleotides--Findings May Have Major Implications for Cancer and Age-Related Conditions

New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works. The findings potentially pave the way for better cancer treatments and revolutionary new drugs that could vastly improve human health in the twilight years. The work, from Assistant Professor of Chemical Engineering and Materials Science Nick Graham, PhD, and his team in collaboration with Scott Fraser, PhD, Provost Professor of Biological Sciences and Biomedical Engineering, and Pin Wang, PhD, Zohrab A. Kaprielian Fellow in Engineering, was published online on May 28, 2019 in the Journal of Biological Chemistry. The article is titled “Inhibition of Nucleotide Synthesis Promotes Replicative Senescence of Human Mammary Epithelial Cells.” "To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing," Dr. Graham said. "We're doing the opposite; we're trying to study the reasons cells age, so that we might be able to design treatments for better aging." To achieve this, lead author Alireza Delfarah, a graduate student in the Graham lab, focused on senescence, a natural process in which cells permanently stop creating new cells. This process is one of the key causes of age-related decline, manifesting in diseases such as arthritis, osteoporosis, and heart disease. "Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division," Delfarah said. "Senescent cells can never divide again. It's an irreversible state of cell cycle arrest." The research team discovered that the aging, senescent cells stopped producing nucleotides, which are the building blocks of DNA.

Newly Identified Pluripotent Liver Cell May Ultimately Provide Alternative to Liver Transplants; Single-Cell RNA Sequencing Key to This Major Discovery

Researchers at King's College London have used single cell RNA sequencing to identify a type of cell that may be able to regenerate liver tissue, treating liver failure without the need for transplants. In a paper published online on July 26, 2019 in Nature Communications, the scientists describe identying a new type of cell called a hepatobiliary hybrid progenitor (HHyP), that forms during our early development in the womb. The open-access article is titled “Single Cell Analysis of Human Foetal Liver Captures the Transcriptional Profile of Hepatobiliary Hybrid Progenitors.” Surprisingly, HHyP also persist in small quantities in adults and these cells can grow into the two main cell types of the adult liver (hepatocytes and cholangiocytes) giving HHyPs stem cell like properties. The team examined HHyPs and found that they resemble mouse stem cells which have been found to rapidly repair mice liver following major injury, such as occurs in cirrhosis. Senior author Dr. Tamir Rashid (photo) from the Centre for Stem Cells & Regenerative Medicine at King's College London said: "For the first time, we have found that cells with true stem-cell-like properties may well exist in the human liver. This in turn could provide a wide range of regenerative medicine applications for treating liver disease, including the possibility of bypassing the need for liver transplants." Liver disease is the fifth biggest killer in the UK and the third most common cause of premature death, and the number of cases is continuing to rise. It can be caused by lifestyle issues such as obesity, viruses, alcohol misuse, or by non-lifestyle issues such as autoimmune and genetic-mediated disease.

Unexpected Developmental Hierarchy Revealed in New Study of Highly Unusual Disease (Langerhans Cell Histiocytosis)--Epigenomics and Single-Cell Sequencing Were Key

Langerhans cell histiocytosis (LCH) is a very unusual disease: Often classified as a cancer because of uncontrolled cell growth in different parts of the body, it also has features of an autoimmune disease, as LCH lesions attract immune cells and show characteristic tissue inflammation. LCH is clinically variable and often difficult to diagnose. Skin involvement in babies with LCH can look like a nappy rash, whereas bone involvement can be mistaken as sarcoma in an X-ray picture. In its most aggressive form, LCH can present as leukemia-like disease and lead to organ failure. These diverse manifestations and the enormous clinical heterogeneity of LCH continue to puzzle medical doctors and scientists around the world. Studying LCH lesions under the microscope, Caroline Hutter, MD, PhD-- a pediatric oncologist at St. Anna Children's Hospital Research Center (CCHR) in Vienna, Austria, principal investigator at CCRI and co-lead investigator of this study -- observed striking heterogeneity among LCH cells. To investigate this diversity in full molecular detail, she assembled an interdisciplinary team including experimental and computational researchers from CCRI and CeMM (Research Center in Molecular Medicine—Vienna Austria), as well as medical doctors from St. Anna Children's Hospital and Vienna General Hospital. Her aim was to answer two fundamental questions: What are the mechanisms behind LCH, and how can we improve treatment of children affected by this disease? Utilizing state-of-the-art technology in the laboratory of co-lead investigator Christoph Bock (CeMM), PhD, LCH lesions were analyzed for their molecular composition at single-cell resolution.

July 26th

CRISPR Activation Screen Identifies Genes That Protect Cells from Zika Virus Infection and Also Prevent Death of Zika-Infected Cells

The Zika virus (image) has affected over 60 million people, mostly in South America. It has potentially devastating consequences for pregnant women and their unborn children, many of whom are born with severe microcephaly and other developmental and neurological abnormalities. There is currently no vaccine or specific treatment for the virus. A new Tel Aviv University (TAU) study uses a genetic screen to identify genes that protect cells from Zika viral infection. The research, led by Dr. Ella H. Sklan of TAU's Sackler School of Medicine, was published online on May 29, 2019 in the Journal of Virology. It may one day lead to the development of a treatment for the Zika virus and other infections. The article is titled “A CRISPR Activation Screen Identifies Genes Protecting from Zika Virus Infection.” The study was based on a modification of the CRISPR-Cas9 gene-editing technique. CRISPR-Cas9 is a naturally occurring bacterial genome editing system that has been adapted to gene editing in mammalian cells. The system is based on the bacterial enzyme Cas9, which can locate and modify specific locations along the human genome. A modification of this system, known as CRISPR activation, is accomplished by genetically changing Cas9 in a way that enables the expression of specific genes in their original DNA locations. "CRISPR activation can be used to identify genes protecting against viral infection," Dr. Sklan says. "We used this adapted system to activate every gene in the genome in cultured cells. We then infected the cells with the Zika virus. While most cells die following the infection, some survived due to the over-expression of some protective genes. We then used next-generation sequencing and bioinformatic analysis to identify a number of genes that enabled survival, focusing on one of these genes called IFI6.

How Pufferfish Developed Its Unusual Spines

Pufferfish are known for their strange and extreme skin ornaments, but how they came to possess the spiky skin structures known as spines has largely remained a mystery. Now, researchers have identified the genes responsible for the evolution and development of pufferfish spines in a study published online on July 25, 2019 in iScience. The open-access article is titled “Evolution and Developmental Diversity of Skin Spines in Pufferfishes.” It turns out that the process is pretty similar to how other vertebrates get their hair or feathers--and might have allowed the pufferfish to fill unique ecological niches. "Pufferfish are some of the strangest fish in the ocean, particularly because they have a reduced skeleton, beak-like dentition and they form spines instead of scales--not everywhere, but just in certain patches around the body," says corresponding author Gareth Fraser (@garethjfraser), PhD, an Assistant Professor at the University of Florida. Dr. Fraser and his team followed the development of pufferfish spines in embryos. While the scientists had initially hypothesized that the spines formed from scales--that the pufferfish lost its scale component but retained the spine--they found that the spines are developmentally unique from scales. They also found that the development of pufferfish spines relies on the same network of genes that are commonly expressed within feathers and hairs of other vertebrate animals. "It just blows me away that regardless of how evolutionarily-different skin structures in animals are, they still use the same collection of genes during development," Dr. Fraser says.