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.
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.
University of British Columbia researchers have identified a small virus that attacks another virus more than 100 times its own size, rescuing the infected zooplankton from certain death. The discovery may provide clues to the evolutionary origin of some jumping genes found in other organisms. The study, by UBC marine microbiologist Dr. Curtis Suttle and Ph.D. student Matthias Fischer, was published online March 3, 2011, in Science Express. It describes the marine virus Mavirus and its interaction with marine zooplankton Cafeteria roenbergenesis and CroV, the world’s largest marine virus. “It’s a microbial version of the David and Goliah story where, after infecting Cafeteria roenbergeneis, Mavirus protects it against infection by CroV, while ensuring its own survival,” said Dr. Suttle. Viruses rely on host cells to replicate; in the case of Mavirus, its host is another virus, making it only the second known virophage. It needs CroV to replicate, and in the process suppresses the propagation of CroV. “What makes this interaction significant to evolutionary biology is that the closest genetic relatives to Mavirus are mobile genetic elements found in single-celled and higher organisms,” said Dr. Suttle. “This implies that over evolutionary time, organisms have co-opted the DNA from ancient relatives of Mavirus into their own genomes, presumably so that they could acquire immunity against giant viruses like CroV. Transposons, or jumping genes, are bits of DNA that can move or “transpose” themselves to new positions within an organism’s genome. Researchers have suspected that a subset of transposons – called Maverick transposons – have a viral origin because of the nature of their DNA sequences. Suttle and Fischer’s latest work on Mavirus provides the first concrete evidence of this connection.
Even long after it is formed, a memory in rats can be enhanced or erased by increasing or decreasing the activity of a particular brain enzyme, say researchers reporting in the March 4 issue of Science. "Our study is the first to demonstrate that, in the context of a functioning brain in a behaving animal, a single molecule, PKMzeta, is both necessary and sufficient for maintaining long-term memory," explained Dr. Todd Sacktor, of the SUNY Downstate Medical Center, New York City, an author of the study, which was partially funded by the NIH. Unlike other recently discovered approaches to memory enhancement, the PKMzeta mechanism appears to work any time. It is not dependent on exploiting time-limited windows when a memory becomes temporarily fragile and changeable – just after learning and upon retrieval – which may expire as a memory grows older, said Dr. Sacktor. "This pivotal mechanism could become a target for treatments to help manage debilitating emotional memories in anxiety disorders and for enhancing faltering memories in disorders of aging," said National Institute of Mental Health (NIMH) Director Dr. Thomas R. Insel, who was not involved in the study. In earlier studies, Dr. Sacktor's team had shown that even weeks after rats learned to associate a nauseating sensation with saccharin and shunned the sweet taste, their sweet tooth returned within a couple of hours after rats received a chemical that blocked the enzyme PKMzeta in the brain's outer mantle, or neocortex, where long-term memories are stored. In the new study, the researchers paired genetic engineering with the same aversive learning model to both confirm the earlier studies and to demonstrate, by increasing PKMzeta, the opposite effect.
New DNA testing technology has allowed scientists to compare the diets of bats consuming food from agricultural environments versus those of bats consuming food from conservation environments. The results indicate that bats feeding in agricultural environments have more restricted diets than do bats feeding in conservation environments. Working at three sites in Southern Ontario (Canada) the research team of students and scientists monitored the diet of little brown bats (Myotis lucifugus) from colonies living on agricultural land and at a conservation site. Guano (bat feces) was continually collected under each roost from May to August. Back in the lab at the Biodiversity Institute of Ontario in Canada, the team extracted insect DNA from the material and sequenced a "DNA barcode" which is a small region of DNA that can be used to identify animal species. The team then matched these unknown insect sequences in bat guano to a library of known sequences to identify which insect prey the bats were eating. "This technology is very new," said lead author Dr. Elizabeth Clare of the University of Bristol's School of Biological Sciences. "It gives us an entirely new insight into the bats' behavior. Instead of just finding they ate a moth or a mayfly, we now know exactly what species of insect it was, providing us with important information on their habitat." Using this technique, the team found that the bats rely heavily on insects from aquatic environments. They were also able to identify the exact species of insect prey, which revealed that different colonies exploit different source water, sometimes rivers and streams, sometimes ponds, depending on the local landscape. "Some of the insects they eat come from very specific habitats and have specific pollution tolerances.
A genome-wide association study has revealed that genetic variation in the neurocan (NCAN) gene is significantly associated with bipolar disorder in thousands of patients. Importantly, in a follow-up study, these findings were replicated in tens of thousands of individual samples of bipolar disorder. The researchers went on to show that the mouse version of this gene, which is written Ncan and is thought to be involved in neuronal adhesion and migration, is strongly expressed in brain areas associated with cognition and the regulation of emotions. Although mice without functional Ncan did not exhibit obvious defects in brain structure or basic cell communication, there did appear to be some perturbation in mechanisms associated with learning and memory, mechanisms that have been associated with the cognitive deficits observed in bipolar disorder. However, the authors caution that Ncan-deficient mice need to be re-examined for more subtle brain changes and behavioral abnormalities. "Our results provide strong evidence that genetic variation in the gene NCAN is a common risk factor for bipolar disorder," concluded Dr. Sven Cichon of the University of Bonn, one of the leaders of the study. "Further work is needed now to learn more about the biological processes that NCAN is involved in and how NCAN variants disturb neuronal processes in patients with bipolar disorder." The NCAN work was published online on February 24, 2011, in the American Journal of Human Genetics. [Press release] [AJHG abstract]
Scientists have reported discovery of a protein in the blood of lung cancer patients that could possibly be used in a test for the disease — difficult to diagnose in its earliest and most treatable stages — and to develop drugs that stop lung cancer from spreading. Their study appears in the American Chemical Society’s Journal of Proteome Research. In the report, Dr. Je-Yoel Cho and colleagues in South Korea note that lung cancer is the leading cause of cancer deaths worldwide. Lung cancer is so deadly because of its tendency to metastasize to distant sites in the body, such as the liver or the brain. Early detection could improve survival rates, but it is very difficult to detect lung cancer at early stages with today's technology. To find a better diagnostic tool, the researchers studied the proteins in the blood of lung cancer patients in search of red flags that could signal the disease's presence. They focused on adenocarcinoma, which accounts for one in three cases and is the most rapidly increasing form of lung cancer in women. Dr. Cho and colleagues found elevated levels of a protein called serum amyloid A (SAA) in the blood and lung tissue of lung adenocarcinoma patients, compared to healthy people. Their work showed that high amounts of SAA were unique to lung cancers (compared with other lung diseases or other cancers) and that the protein was involved in metastasis of cancer cells from the original tumor site. The researchers said that the protein could be used as a diagnostic marker for lung cancer and as a target for developing drugs that stop metastasis. [Press release] [Journal of Proteome Research abstract]
A promising new way to potentially inhibit cholesterol production in the body has been discovered, a way that may yield treatments as effective as existing medications but with fewer side-effects. In a study published in the March 2 issue of the journal Cell Metabolism, a team of researchers from the University of New South Wales (UNSW) School of Biotechnology and Biomolecular Sciences-led by Associate Professor Andrew Brown–report that an enzyme-squalene mono-oxygenase (SM)-plays a previously unrecognized role as a key checkpoint in cholesterol production. SM is one of at least 20 enzymes involved in the assembly line when cholesterol is made throughout the body but only one of these enzymes-HMG-CoA reductase (HMGR)–is currently targeted by medications to lower cholesterol levels in the blood. "The class of drugs most commonly used to lower cholesterol-statins–are the blockbusters of the pharmaceutical world and work by inhibiting HMGR," said Professor Brown. "But HMGR is involved very early on in the assembly line, so inhibiting it affects all the other steps down the line–and other useful products it provides-and that can give rise in some people to unwanted side-effects, such as muscle pain. What's exciting about this previously overlooked SM enzyme is that it acts as a checkpoint much further down the assembly line, which should mean that it can be more specifically targeted at cholesterol production instead and leave the early part of the assembly line undisturbed. Cholesterol has developed something of a bad name, so many people don't realize that it is actually essential for a healthy body. It's needed, for example, to make sex hormones and to help build the walls of every single cell in our bodies."
A multinational study has identified four mutations in a single key gene as responsible for type 2 diabetes in nearly 10 percent of patients of white European ancestry. The study, which originated in Italy and was validated at the University of California-San Francisco (UCSF) and the University of Reims, found that defects in the HMGA1 gene led to a major drop in the body’s ability to make insulin receptors – the cell’s sensor through which insulin tells the cell to absorb sugar. This drop in insulin receptors leads to insulin resistance and type 2 diabetes, according to the paper, which was published online on March 2 in JAMA. Until now, no mutations in a single gene have been significantly associated with playing a role in type 2 diabetes. The results provide the unique opportunity for a test to predict potential for the disease in patients, as well as the possibility of identifying which of the current diabetes medications work best for people with one of the gene mutations, the authors said. Ultimately, it also could help drive research to find new and improved drugs for those patients. While the study focused on Caucasians, it also lays the groundwork for similar analyses in patients of Asian, African, and Native American descent, who suffer from higher rates of the disease, according to diabetes researcher Dr. Ira Goldfine, a UCSF professor of medicine and of physiology who led the U.S. arm of these studies. “This is a major breakthrough in type 2 diabetes,” said Dr. Goldfine, noting that 26 million Americans have diabetes and an estimated 79 million have pre-diabetes. “Many of our current diabetes drugs are very effective in some patients and not in others.
Researchers led by Dr. Dan Frenkel of Tel Aviv University's Department of Neurobiology are working on a nasally-delivered 2-in-1 vaccine that promises to protect against both Alzheimer's and stroke. The new vaccine repairs vascular damage in the brain by rounding up "troops" from the body's own immune system. And in addition to its prophylactic effect, study results suggest that the vaccine can have beneficial effects even when Alzheimer's symptoms are already present. The research on this new technology was recently accepted for publication in the journal Neurobiology of Aging. "Using part of a drug that was previously tested as an influenza drug, we've managed to successfully induce an immune response against amyloid proteins in the blood vessels," said Dr. Frenkel, who collaborated on this project with Professor Howard L. Weiner of Brigham and Women's Hospital, Harvard Medical School. "In early pre-clinical studies, we've found it can prevent both brain tissue damage and restore cognitive impairment," Dr. Frenkel added. Modifying a vaccine technology owned by Glaxo Smith Kline, a multinational drug company, Tel Aviv University's new therapeutic approach activates a natural mechanism in our bodies that fights against vascular damage in the brain. The vaccine, Dr. Frenkel explained, activates macrophages — phagocytic cells in the body that swallow foreign antigens. When the vaccine activates large numbers of these macrophages, they clear away the damaging build-up of waxy amyloid proteins in the brain's vascular system. Studies in animal models showed that once these proteins are cleared from the brain, further damage can be prevented, and existing damage due to a previous stroke can be repaired.