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Archive - 2011

March 8th

Nobelist’s New Work Shows Compound Rids Animal Cells of Alzheimer Protein Debris

If you can't stop the beta-amyloid protein plaques from forming in Alzheimer's disease patients, then maybe you can help the body rid itself of them instead. At least that's what scientists from New York were hoping for when they found a drug candidate to do just that. Their work appears in a research report online on March 2, 2011, in The FASEB Journal, and shows that a new compound, called "SMER28" stimulated autophagy in rat and mice cells. Autophagy is a process cells use to "clean out" the debris from their interior, including unwanted materials such as the protein aggregates that are hallmarks of Alzheimer's disease. In mice and rat cells, SMER28 effectively slowed down the accumulation of beta-amyloid. "Our work demonstrates that small molecules can be developed as therapies, by activating a cellular function called autophagy, to prevent Alzheimer's disease," said senior author Dr. Paul Greengard, Nobel laureate and director of the Laboratory of Molecular and Cellular Neuroscience at The Rockefeller University in New York, NY. "By increasing our understanding of autophagy, it might be possible to stimulate it pharmacologically or naturally to improve the quality of life for aging people." Using mouse and rat cells, scientists tested various compounds for their ability to reduce the buildup of beta-amyloid by exposing cultured cells to compounds known to activate autophagy. The effects of these compounds were then compared by removing growth factors from the culture medium. Researchers then focused on the most effective compound, which was SMER28, to characterize the cellular components involved in this phenomenon. For that purpose, the effect of SMER28 on beta-amyloid formation was compared using normal cells or cells where the expression of genes known to be involved in autophagy was reduced or abolished.

Psoriasis Medication May Be Useful in Treating Multiple Sclerosis

Fumaric acid salts have been in use against severe psoriasis for a long time. About ten years ago, researchers in Bochum, Germany, speculated that they may also have a favorable effect on multiple sclerosis (MS) as a result of their Th2 polarizing mechanisms. In parallel to phase III studies, researchers have been actively searching for the precise effective mechanisms. This has now been achieved by a neuroimmunological group at Bochum: fumaric acid salts detoxify radicals released during the inflammation process. In this way, they protect nerve and glial cells. Neurologists at the Ruhr University Hospital, St. Josef Hospital, working with Professor Ralf Gold, report these findings in the March 3 issue of the leading neurology journal BRAIN. As MS, psoriasis is an auto-immune disease, in which the immune system attacks the body's own cells. In MS, the insulating myelin layer of the axons is destroyed in this way. About ten years ago, the Ruhr University Bochum dermatologist Professor Peter Altmeyer informed his colleague, the neurologist Professor Horst Przuntek, that the mixture of fumaric acid salts registered for treatment of psoriasis under the trade name FUMADERM could possibly exert favorable effects in MS as well. In turn, the Swiss manufacturer Fumapharm sponsored a small study in Bochum. Ten patients were examined for a period of 48 weeks (Schimrigk et al European Journal of Neurology 2006, 13: 604). In parallel to this, Fumapharm supported basic research which Professor Gold then performed at his MS Institute in Göttingen (Schilling et al. Clin. Exp. Immunology 2006; 145: 101-107). After that, the scenario moved rapidly: the US pharmaceutical company BiogenIdec with its focus in MS research took over Fumapharm AG and initiated a successful Phase II study (Kappos, Gold, Lancet 2008; 372: 1463).

Putrescine Protects Brain from Epileptic Seizures in Tadpole Studies

For years, brain scientists have puzzled over the shadowy role played by the molecule putrescine, which always seems to be present in the brain following an epileptic seizure, but without a clear indication whether it was there to exacerbate brain damage that follows a seizure or protect the brain from it. A new Brown University study unmasks the molecule as squarely on the side of good: It seems to protect against seizures hours later. Putrescine is a foul-smelling organic chemical compound (1,4-diaminobutane or butanediamine) that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses. The two compounds are largely responsible for the foul odor of putrefying flesh. Putrescine is one in a family of molecules called "polyamines" that are present throughout the body to mediate crucial functions such as cell division. Why they surge in the brain after seizures isn't understood. In a lengthy set of experiments, Brown neuroscientists meticulously traced their activity in the brains of seizure-laden tadpoles. What they found is that putrescine ultimately is converted into the neurotransmitter GABA, which is known to calm brain activity. When the researchers caused a seizure in the tadpoles, they found that the putrescine produced in a first wave of seizures helped tadpoles hold out longer against a second wave of induced seizures. Dr. Carlos Aizenman, assistant professor of neuroscience and senior author of the study published online on March 6, 2011, in the journal Nature Neuroscience, said further research could ultimately produce a drug that targets the process, potentially helping young children with epilepsy. Tadpoles and toddlers aren't much alike, but this basic aspect of their brain chemistry is.

March 7th

Clinical Observation Yields Molecular Insight into Lung Cancer

A discovery at University of Colorado Cancer Center shows testing lung cancer on a molecular level may produce new insights into this deadly disease. Cancer Center member Dr. D. Ross Camidge, director of the thoracic oncology clinical program at University of Colorado Hospital (UCH), turned a chance clinical observation into a new field of discovery in lung cancer. In October 2010, Dr. Camidge and colleagues published a study in the New England Journal of Medicine showing more than half of patients with a specific kind of lung cancer respond positively to a treatment that targets the gene that drives their cancer. Fifty-seven percent of patients with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer responded to a tablet called crizotinib, an investigational ALK inhibitor. Camidge's latest study, published in the Journal of Thoracic Oncology, shows people with ALK-positive lung cancer also have much better outcomes with an established chemotherapy drug called pemetrexed (trade name: alimta). "We had been running a home-grown clinical trial with pemetrexed in lung cancer when I noticed that some patients were doing astonishingly well on this chemotherapy," said Dr. Camidge, associate professor of medical oncology at the University of Colorado School of Medicine. "Pemetrexed is not like most other chemotherapies. It can be given for long periods of time, often with little in the way of side-effects. However, when someone is given pemetrexed, on average it only takes three to four months before their cancer starts to grow again. But certain people in this trial were responding to the treatment for a year or more. When we started to test their cancers at the molecular level, almost all of those 'super-survivors' turned out to be ALK-positive.

March 6th

13 Gene Regions Newly Associated with Coronary Atherosclerosis in Massive Study

Thirteen new gene regions have been convincingly associated with coronary atherosclerosis in a massive, new, international genetics study involving investigators from the Stanford University School of Medicine and researchers from other major institutions around the world. The results of the study, published online March 6 in Nature Genetics, provide 13 vital new clues on the etiology of this disease, the most common cause of death worldwide. The study doubles the number of gene regions previously known to predispose people to this condition. Coronary atherosclerosis is the process by which plaque builds up in the wall of heart vessels, eventually leading to chest pain and potentially lethal heart attacks. The study was conducted by an international consortium, which pooled resources to analyze data from 14 genome-wide association studies. Consortium investigators examined the complete genetic profiles of more than 22,000 people of European descent with coronary heart disease or a heart attack history and 60,000 healthy people — close to 10 times more than the next-largest whole-genome study to date. "These new discoveries will allow scientists worldwide to eventually better understand the root causes of coronary atherosclerosis, possibly leading to important new drug therapies that may profoundly reduce the risk of having a heart attack," said Dr. Thomas Quertermous, the William G. Irwin Professor in Cardiovascular Medicine at Stanford. Dr. Quertermous is the principal investigator of the Stanford/Kaiser ADVANCE study of heart disease, which joined this consortium early in its formation. Investigators were able to examine an average of 2.5 million common single nucleotide polymorphisms, or SNPs, in each of the 14 genome-wide association studies. SNPs are genetic variants at specific locations on individual chromosomes.

Gene for Rare Osteoporosis Disorder Identified

Scientists have identified a single mutated gene that causes Hajdu-Cheney syndrome (HCS), a disorder of the bones causing progressive bone loss and osteoporosis. The study, published online in Nature Genetics on March 6, 2011, gives vital insight into possible causes of osteoporosis and highlights the identified gene (NOTCH2) as a potential target for treating the condition. There are only 50 reported cases of HCS, of which severe osteoporosis is a main feature. Osteoporosis is a condition leading to reduction in bone strength and susceptibility to fractures. It is the most common bone disease, with one in two women and one in five men over 50 in the UK fracturing a bone because of the condition. This represents a major public health problem yet, until this study, possible genetic causes of osteoporosis have been poorly understood. The team of researchers, led by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) at King's College London and Guy's and St Thomas', set out to investigate the genetic cause of HCS in order to detect clues to the role genes might play in triggering osteoporosis. Using a cutting edge technique for identifying disease-causing genes, known as exome sequencing, the team was able to identify NOTCH2 as the causative gene using DNA from just three unrelated HCS patients. The team then confirmed their findings in an additional 12 affected families, 11 of whom had an alteration in the identical portion of the same gene. Senior author Professor Richard Trembath, Head of King's College London's Division of Genetics and Molecular Medicine and Medicine Director of the NIHR BRC, said: "Up until now, we knew very little about the genetic mechanisms of severe bone disease.

Cryo-Microscope Allows High-Res 3-D Model of Salmonella’s Needle Complex

Some of the most dread diseases in the world such as plague, typhoid, and cholera are caused by bacteria that have one thing in common: they possess an infection apparatus which is a nearly unbeatable weapon. When attacking a cell of the body, they develop numerous hollow-needle-shaped structures that project from the bacterial surface. Through these needles, the bacteria inject signal substances into the host cells, which re-program these cells and thereby overcome their defense. The pathogens can then invade the cells unimpeded and in large numbers. The biochemist and biophysicist Dr. Thomas Marlovits, a group leader at the Vienna Institutes IMP (Research Institute of Molecular Pathology) and IMBA (Institute of Molecular Biotechnology) has been occupied for several years with the infection complex of salmonellae. As early as in 2006 Dr. Marlovits showed how the needle complex of Salmonella typhimurium develops. Together with his doctoral student Oliver Schraidt, he has now been able to demonstrate the three-dimensional structure of this complex at extremely high resolution. The team was able to show details with dimensions of just 5 to 6 angstroms, which are nearly atomic orders of magnitude. Their work is presented in the March 4, 2011 issue of Science. Never before has the infection tool of salmonellae been presented in such precision. This was achieved by the combined use of high-resolution cryo-electron microscopy and specially developed imaging software. "Austria's coolest microscope" makes it possible to shock-freeze biological samples at minus 196 degrees centigrade and view them in almost unchanged condition.

March 5th

Novel Mechanism for Control of Gene Expression

Researchers at Boston University have discovered a novel, evolutionarily conserved mechanism for the regulation of gene expression. The new work by Dr. David Levin and Dr. Ki-Young Kim is reported in the March 4, 2011 issue of Cell. Normal cell growth, embryonic development, and responses to stress, require proper spatial and temporal control of gene expression. Studies on control of transcription (RNA biosynthesis) are typically centered on understanding how the RNA polymerase is recruited to the promoter, the control region of a gene. However, the new work has revealed the existence of a second level of control in a yeast model system. The researchers found that genes expressed solely under certain stress conditions are normally maintained in a silent state by a process called transcriptional attenuation. In attenuation, the RNA polymerase initiates transcription of the gene, but its progress is terminated prematurely by a termination complex that binds to the polymerase. Attenuation occurs commonly in bacteria, but was not previously known to operate in eukaryotic cells (those with a nucleus). “In response to an inducing stress signal, attenuation must be overcome so that a target gene can be expressed,” said Dr. Levin. “The way that works in this instance is that an activating transcription factor, called Mpk1, serves double duty—it is first responsible for recruitment of the RNA polymerase to the promoter, but Mpk1 then binds to the transcribing polymerase to block association of the termination complex.” Mutations in a human protein, called Senataxin, which is related to a component of the yeast termination complex, are responsible for causing juvenile-onset forms of ALS and ataxia, two neuromuscular degenerative diseases. In their new research, Dr. Levin and Dr.

New Details on Key Protein in Lou Gehrig’s Disease

Amyotrophic lateral sclerosis, known as ALS or more popularly, Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death. In a new paper, published in the Feb. 27 advance online edition of the journal Nature Neuroscience, a team of scientists at the University of California, San Diego School of Medicine and colleagues describe the profound and pervasive role of a key RNA-binding protein called TDP-43 in ALS pathology. It has previously been shown that, when mutated, TDP-43 can cause ALS. The new work on TDP-43 was led by Dr. Don W. Cleveland, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and Dr. Gene Yeo, assistant professor in the Department of Cellular and Molecular Medicine. In normal cells, TDP-43 is found in the nucleus where it helps maintain proper levels of RNA. In the majority of ALS patients, however, TDP-43 accumulates in the cell's cytoplasm and thus is excluded from the nucleus, which prevents it from performing its normal duties. Using a mouse model, the researchers made three new important findings: First, employing a comprehensive genome-wide RNA-binding mapping strategy, they discovered that more than one-third of the genes in the mouse brain are direct targets of TDP-43. In other words, the roles and functions of these genes are impacted by the presence – or absence – of normal TDP-43. Second, the genes most affected had numerous TDP-43 binding sites on very long introns. Introns are the non-coding portions of a gene that are not used to make proteins.

March 4th

Possible Liver Origin of Alzheimer’s Plaques

Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists' ideas about Alzheimer's disease—pointing to the liver instead of the brain as the source of the "amyloid" that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment. The study was published online on March 3, 2011, in The Journal of Neuroscience Research. In the study, the scientists used a mouse model for Alzheimer's disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin—a cell membrane protein believed to contribute to the development of human Alzheimer's. "This unexpected finding holds promise for the development of new therapies to fight Alzheimer's," said Scripps Research Professor Greg Sutcliffe, who led the study. "This could greatly simplify the challenge of developing therapies and prevention." In trying to help solve the Alzheimer's puzzle, in the past few years Dr. Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes. As is the case with nearly all scientific discovery, Dr. Sutcliffe's research builds on previous findings.