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Clue to Mechanism by Which Certain Gene Mutations Cause Familial Parkinson’s

Researchers at the Mount Sinai School of Medicine and collaborating institutions have discovered a way that mutations in a gene called LRRK2 may cause the most common inherited form of Parkinson's disease. The study, published online on March 1, 2011, in the journal PLoS ONE, shows that upon specific modification called phosphorylation, LRRK2 protein binds to a family of proteins called 14-3-3, which has a regulatory function inside cells. When there is a mutation in LRRK2, 14-3-3 is impaired, leading to Parkinson's. This finding explains how mutations lead to the development of Parkinson's, providing a new diagnostic and drug target for the disease. Using one-of-a-kind mouse models developed at the Mount Sinai School of Medicine, Dr. Zhenyu Yue, Associate Professor of Neurology and Neuroscience, and his colleagues, found that several common Parkinson's disease mutations—including one called G2019S—disturb the specific phosphorylation of LRRK2. This impairs 14-3-3 binding to varying degrees, depending on the type of mutation. "We knew that the LRRK2 mutation triggers a cellular response resulting in Parkinson's disease, but we did not know what processes the mutation disrupted," said Dr. Yue. "Now that we know that phosphorylation is disturbed, causing 14-3-3 binding to be impaired, we have a new idea for diagnostic analysis and a new target for drug development." Dr. Yue's team also identified a potential enzyme called protein kinase A (PKA), responsible for the phosphorylation of LRRK2. Although the exact cellular functions disrupted by these changes are unclear, the study provides a starting point for understanding brain signaling that contributes to the disease.

Potential Non-Insulin Treatment of Type 1 Diabetes Investigated

Researchers at the University of Texas Southwestern Medical Center have discovered a hormone pathway that potentially could lead to new ways of treating type 1 diabetes independent of insulin, long thought to be the sole regulator of carbohydrates in the liver. Results of this new study are published in the March 25, 2011 issue of Science. Another hormone, fibroblast growth factor 19 (FGF19), has insulin-like characteristics beyond its role in bile acid synthesis. Unlike insulin, however, FGF19 does not cause excess glucose to turn to fat, suggesting that its activation could lead to new treatments for diabetes or obesity. “The fundamental discovery is that there is a pathway that exists that is required for the body, after a meal, to store glucose in the liver and drive protein synthesis. That pathway is independent of insulin,” said Dr. David Mangelsdorf, chairman of pharmacology at UT Southwestern. Naturally elevating this pathway, therefore, could lead to new diabetes treatments outside of insulin therapy. The standard treatment for type 1 diabetes, which affects about 1 million people in the U.S., involves taking insulin multiple times a day to metabolize blood sugar. Dr. Mangelsdorf and Dr. Steven Kliewer, professor of molecular biology and pharmacology at UT Southwestern, are co-senior authors of the study. Dr. Kliewer has been studying the hormone FGF19 since he discovered its involvement in metabolism about eight years ago. Fibroblast growth factors control nutrient metabolism and are released upon bile acid uptake into the small intestine. Bile acids, produced by the liver, break down fats in the body. In this work, researchers studied mice lacking FGF15 – the rodent FGF19 hormone equivalent. These mice, after eating, could not properly maintain blood concentrations of glucose and normal amounts of liver glycogen.

MicroRNAs Implicated in Panic Disorder

Studies in twin pairs suggest that 40% of the risk for panic disorder is heritable, yet the manner in which genes contribute to the risk for panic disorder is far from clear. To date, variations in a growing number of genes have been implicated in the risk for panic disorder, but the magnitude of the impact of each individual gene is relatively small. The pattern of these implicated genes raises the question of whether there might be molecular "switches" that control the function of groups of genes in a coordinated fashion, which would help to explain the observed findings related to the genetics of panic disorder. A new study published in the March 15, 2011 issue of Biological Psychiatry now implicates one type of molecular switch, microRNAs (miRNAs), in panic disorder. miRNAs are small bits of RNA that bind to DNA and control the expression of various genes. There are a large number of miRNAs that have diverse effects on gene expression. Through case-control studies in three different populations, from Spain, Finland, and Estonia, Dr. Margarita Muiños-Gimeno, Dr. Yolanda Espinosa-Parrilla, and colleagues found that at least four miRNAs (miR-22, miR-138-2, miR-148a, and miR-488) may be involved in the pathophysiology of panic disorder. Their subsequent functional studies revealed that miR-138-2, miR-148a and miR-488 repress several candidate genes for panic disorder including GABRA6, CCKBR and POMC, respectively, and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Their analysis also implicated miR-22 and miR-488 in the regulation of anxiety-related pathways in the brain. "These data provide important new evidence that variation in genes coding for miRNAs may coordinate the involvement of a number of risk genes and thereby contribute to the development of panic disorder," commented Dr.

UCSF Researchers ID Compounds That Regulate Fat Storage in Worms

Researchers exploring human metabolism at the University of California, San Francisco (UCSF) have identified a handful of chemical compounds that regulate fat storage in worms, offering a new tool for understanding obesity and finding future treatments for diseases associated with obesity. As described in a paper published March 13, 2011, in the journal Nature Chemical Biology, the UCSF team took armies of microscopic worms called C.elegans and exposed them to thousands of different chemical compounds. Giving these compounds to the worms, they discovered, basically made them skinnier or fatter without affecting how they ate, grew, or reproduced. The discovery gives scientists new ways to investigate metabolism and could eventually lead to the development of new drugs to regulate excessive fat accumulation and address the metabolic issues that underlie a number of major human health problems, including, obesity, diabetes and some forms of cancer. The work also demonstrates the value of "worm screening" as a way of finding new targets for human diseases, according to the UCSF scientists, whose work was spearheaded by postdoctoral fellow Dr. George Lemieux, in the laboratory of Professor Zena Werb, vice chair of the Department of Anatomy at UCSF. The work was a collaboration also involving Dr. Kaveh Ashrafi, an associate professor in the UCSF Department of Physiology, and Dr. Roland Bainton, an associate professor in residence in the UCSF Department of Anesthesia & Perioperative Care. The UCSF team's interest in how worms deal with fat began with a more fundamental interest in human metabolism. Worms make molecules of fat for the same reasons humans do – they are useful for storing energy and are a basic building block for body tissues.

Progress Toward Stem Cell Therapy for Macular Degeneration

The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration (AMD) has taken a significant step toward becoming a reality. In a study published March 24, 2011, in Stem Cells, Georgetown University Medical Center (GUMC) researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight. AMD is a leading cause of visual impairment and blindness in older Americans and worldwide. AMD gradually destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina. While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient's own stem cells to generate tissues and cells for transplantation. For transplantation to be viable in AMD, researchers have to first determine how to program the naïve hiPS cells to function and possess the characteristics of the native RPE, the cells that die off and lead to AMD. The research conducted by the Georgetown scientists shows that this critical step in regenerative medicine for AMD has greatly progressed. "This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration," says the study's lead author Dr. Nady Golestaneh, assistant professor in GUMC's Department of Biochemistry and Molecular & Cellular Biology.

Short Telomeres May Predispose to Diabetes

New evidence has emerged from studies in mice that short telomeres or "caps" at the ends of chromosomes may predispose people to age-related diabetes, according to Johns Hopkins scientists and colleagues. Telomeres are repetitive sequences of DNA that protect the ends of chromosomes, and they normally shorten with age, much like the caps that protect the ends of shoelaces. As telomeres shorten, cells lose the ability to divide normally and eventually die. Telomere shortening has been linked to cancer, lung disease, and other age-related illnesses. Diabetes, also a disease of aging, affects as many as one in four adults over the age of 60. The Johns Hopkins research, described online on March 10, 2011, in PLoS ONE, arose from Dr. Mary Armanios' observation that diabetes seems to occur more often in patients with dyskeratosis congenita, a rare, inherited disease caused by short telomeres. Patients with dyskeratosis congenita often have premature hair graying and are prone to develop early organ failure. "Dyskeratosis congenita is a disease that essentially makes people age prematurely. We knew that the incidence of diabetes increases with age, so we thought there may be a link between telomeres and diabetes," said Dr. Armanios, assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. Dr. Armanios studied mice with short telomeres and their insulin-producing beta cells. Human diabetics lack sufficient insulin production and have cells resistant to its efficient use, causing disruption to the regulation of sugar levels in the blood. Dr. Armanios found that despite the presence of plentiful, healthy-looking beta cells in the mice, they had higher blood sugar levels and secreted half as much insulin as the controls.

Telomerase Inhibitor Proves to Be Key Tumor Suppressor

It's been nearly 10 years since Beth Israel Deaconess Medical Center (BIDMC) scientists Dr. Kun Ping Lu and Dr. Xiao Zhen Zhou discovered PinX1, the first potent endogenous protein shown to inhibit telomerase in mammals. Now the scientific team has discovered a vitally important new function for this telomerase inhibitor. The investigators report online on March 23, 2011, in the Journal of Clinical Investigation (JCI) that low levels of PinX1 contribute to cancer development, providing the first genetic evidence linking telomerase activation to chromosome instability and cancer initiation, and suggesting a new avenue of treatment for cancers. "Although telomerase is activated in 85 to 90 percent of human cancers, little has been known about the significance of telomerase activation in chromosome instability and cancer initiation," explains Dr. Lu, the paper's senior author and a Professor of Medicine at Harvard Medical School. "We have discovered, for the first time, a novel role for abnormal telomerase activation in cancer initiation. This suggests that telomerase inhibition using PinX1 or other small molecules may be used to treat certain cancers with activated telomerase." Of particular note, the group's discovery that most PinX1-mutant mouse tumors share tissues of origin with human cancer types linked to genetic alterations in chromosome 8p23 suggests a possible role for deregulation of the PinX1-telomerase complex for the treatment of several common carcinomas, including breast, lung, liver, and gastrointestinal cancers. Telomeres cap the ends of linear chromosomes and are essential for maintaining chromosome stability. In the majority of human cells, telomeres are slightly shortened each time a cell divides, a process that, over time, leads to cell death.

Zebrafish Model Reveals New Gene for Human Melanoma

Looking at the dark stripes on the tiny zebrafish you might not expect that they hold a potentially important clue for discovering a treatment for the deadly skin disease melanoma. Yet melanocytes, the same cells that are responsible for the pigmentation of zebrafish stripes and for human skin color, are also where melanoma originates. Dr. Craig Ceol, assistant professor of molecular medicine at the University of Massachusetts Medical School, and collaborators at several institutions, used zebrafish to identify a new gene responsible for promoting melanoma. In a paper featured on the cover of the March 24 issue of Nature, Dr. Ceol and colleagues describe the melanoma-promoting gene SETDB1, which codes for a methyl transferase. "We've known for some time that there are a number of genes that are responsible for the promotion and growth of melanoma," said Dr. Ceol, who completed the research while a postdoctoral fellow in the lab of Howard Hughes Medical Institute investigator Dr. Leonard Zon at Children's Hospital Boston. "With existing methods, it had been difficult to identify what those genes are. By developing the new approach described in this paper, we were able to isolate SETDB1 as one of those genes." Cases of melanoma, an aggressive form of skin cancer, have been on the rise in the United States: in 2009 alone, 68,000 new cases were diagnosed and 8,700 people died of the disease. Though it accounts for less than 5 percent of all skin cancers, it is responsible for the majority of deaths from skin cancers and has a poor prognosis when diagnosed in its advanced stages. Early signs of melanoma include changes to the shape or color of existing moles or the appearance of a new lump anywhere on the skin.

Epigenomic Findings Have Implications for Common Disease Studies

Genes make up only a tiny percentage of the human genome. The rest, which has remained measurable but mysterious, may hold vital clues about the genetic origins of disease. Using a new mapping strategy, a collaborative team led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and MIT has begun to assign meaning to the regions beyond our genes and has revealed how minute changes in these regions might be connected to common diseases. The researchers' findings appeared online on March 23, 2011 in Nature. The results have implications for interpreting genome-wide association studies (GWAS) – large-scale studies of hundreds or thousands of people in which scientists look across the genome for single "letter" changes or SNPs (single nucleotide polymorphisms) that influence the risk of developing a particular disease. The majority of SNPs associated with disease reside outside of genes and, until now, very little was known about the functions of most of them. "Our ultimate goal is to figure out how our genome dictates our biology," said co-senior author Dr. Manolis Kellis, a Broad associate member and associate professor of computer science at MIT. "But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation." The term "epigenome" refers to a layer of chemical information on top of the genetic code, which helps determine when and where (and in what types of cells) genes will be active. This layer of information consists of chemical modifications, or "chromatin marks," that appear across the genetic landscape of every cell, and can differ dramatically between cell types.

Trigger Found for Autoimmune Heart Attacks

People with autoimmune type 1 diabetes, whose insulin-producing cells have been destroyed by the body's own immune system, are particularly vulnerable to a form of inflammatory heart disease (myocarditis) caused by a different autoimmune reaction. Scientists at the Joslin Diabetes Center have now revealed the exact target of this other onslaught, taking a large step toward potential diagnostic and therapeutic tools for the heart condition. Researchers in the lab of Dr. Myra Lipes, have shown in both mice and people that myocarditis can be triggered by a protein called alpha-myosin heavy chain, which is found only in heart muscle and in especially low quantities in human heart tissue. While myocarditis often follows viral attacks or other infections, Dr. Lipes and her colleagues previously demonstrated that mice genetically modified to model type 1 diabetes could generate myocarditis spontaneously. In their latest work, reported online on March 23, 2011, in the Journal of Clinical Investigation, the scientists analyzed blood from such mice and identified two types of autoimmune response directed specifically against the protein, with the first response directed by a specialized kind of immune system cells called T cells and the second by antibodies. In both mice and people, T cells are "trained" by specialized cells in the thymus, a small organ in front of the heart, to recognize the body's own cells and refrain from attacking them. The researchers found, however, that in mice these specialized training cells couldn't train on the alpha-myosin heavy chain protein because none of that protein was being produced in those cells. Next, the scientists showed that the disease didn't develop in similar mice that were genetically engineered to produce the protein in the specialized training cells.

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