Mayo Clinic in Jacksonville
Thursday, September 27, 2007
JACKSONVILLE, Fla. — Researchers at Mayo Clinic in Jacksonville have discovered how loss of a gene can lead to accumulation of toxic proteins in the brain, resulting in a common dementia, and they say this mechanism may be important in a number of age-related neurological disorders.
In the Sept. 26 issue of the Journal of Neuroscience, the scientists demonstrate that absence of a gene known as progranulin leads to errant splicing of a protein that usually operates within the nucleus of a nerve cell (neuron). When cut these proteins move into the body of the cell, and begin to stick together and form a thicket that grows, eventually disrupting the normal functioning of the neuron, the researchers say.
Clumps of this protein, TDP-43, have been found in a number of older age dementias, including Alzheimer’s Disease (AD), Frontal Temporal Dementia (FTD), and in amyotrophic lateral sclerosis (ALS).
Not only does the study potentially explain why TDP-43 pathology is present in a number of neurodegenerative diseases, it also offers new research routes to take in looking for beneficial treatments, says the study’s lead investigator, Leonard Petrucelli, Ph.D. “Our work opens opportunities on possible future therapeutic applications, from approaches to novel drug discovery to the continued exploration of cell survival systems,” he says.
Mayo investigators filled in this piece of the dementia puzzle by exploring possible connections between two recent ground-breaking discoveries. In July, 2006, Mayo researchers reported in Nature that a form of FTD not caused by tau accumulation in neurons was due to mutations in the progranulin gene. Progranulin produces a protein that helps neurons survive, and so far, the research group has found more than 40 different mutations in the gene can directly cause FTD.
The second study, reported in October, 2006, in Science by researchers at the University of Pennsylvania School of Medicine, found that the protein clogging brains of patients with FTD and ALS is TDP-43. The protein was recovered from post-mortem brain tissue and was found only in areas affected by the diseases. For example, in ALS patients it was found in the spinal cord motor neurons which control movement, and in patients with FTD, which is second most common form of dementia in people under age 65, clumps of TDP-43 were found in the frontal and temporal lobes which control the judgment and thought process disrupted in the disease. In its normal state, TDP-43 is believed to help genes produce proteins.
In this study, Mayo researchers investigated whether progranulin is involved in TDP-43 processing. Suppressing progranulin expression in neurons led to accumulation of TDP-43 fragments, they found, and further discovered that this cleavage depends on the caspase 3 enzyme. Caspases cut other proteins and thus play a crucial role in pushing a cell to die when it needs to. It makes sense that these caspase might be activated when progranulin is mutated, Dr. Petrucelli says, because loss of progranulin can activate cell death signaling. “We are now looking into how mutations in progranulin leads to an increase in caspase activity,” he says. “Progranulin could be acting a protective chaperone where it binds to TDP-43, and may protect it from cleavage.”
Theoretically, suppression of caspase 3 might stop the cutting and accumulation of TDP-43, but such a strategy could not work clinically given that caspases are needed throughout the body for normal functioning, Dr. Petrucelli says. “However, it might be possible to identify other compounds that specifically prevent the fragmentation and redistribution of TDP-43, and that is an issue we are now studying.”
At this point, researchers don’t know if progranulin mutations are present in ALS or in AD.
The study was funded by the Mayo Clinic Foundation and by the National Institute on Aging, part of the National Institutes of Health. In this study, Yong-Jie Zhang, Ph.D., and Ya-fei Xu, M.D., both of whom contributed equally as first authors, and other Mayo Clinic, Jacksonville, contributors include Dennis Dickson, M.D., and Rachel Bailey, B.S. Other authors include Chad Dickey, Ph.D., from the University of South Florida; Emanuele Buratt,i Ph.D., and Francisco Baralle, M.D., from the International Center for Genetic Engineering and Biotechnology in Trieste, Italy; and Stuart Pickering-Brown, Ph.D., from the University of Manchester in the United Kingdom.
To obtain the latest news releases from Mayo Clinic, go to http://www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories.
For more information, contact:
Media Contact: Ron Walli
Communications and External Relations
OAK RIDGE, Tenn., Aug. 29, 2007 — Mice that are part of the Collaborative Cross project at Oak Ridge National Laboratory are helping scientists around the world learn more about possible causes of drug abuse, diabetes, sleep disorders, stress and pain, kidney disease and a number of other conditions that affect millions of people.
The Collaborative Cross, begun in 2005 with a grant from the Ellison Medical Foundation, represents a fundamentally new way of conducting genetics research and aims to create 1,000 strains of mice that feature the genetic diversity of the world population. When completed in about five years, the research community will have access to an extremely versatile resource plus data that is the click of a mouse away. There will be other benefits as well.
“With our new facility at ORNL, we offer economies of scale for the production of populations of mice,” said Elissa Chesler, leader of the systems genetics group in the Biosciences Division. “Without having to maintain their own mouse colonies, researchers will have access to mice that will enable them to do experiments that cannot be done anywhere else.”
While conventional genetics studies have primarily involved stand-alone experiments aimed at discovering single gene variants, the Collaborative Cross represents the new approach that researchers say is necessary to develop a community resource for understanding the genetic and environmental complexity of human diseases. With this approach, using a reference population that allows for high genetic diversity and large sample size, researchers can more effectively examine combinations of genes responsible for diseases. This combination is what makes the Collaborative Cross special.
“We can stop blaming single genes for causing diseases,” Chesler said. “We now know that bad combinations of normal genes are at fault, and this mouse population will make it possible to determine complex causes and to develop drugs to treat those diseases.”
In one experiment at ORNL, William Lariviere of the University of Pittsburgh School of Medicine hopes to find genes that cause some people to be more sensitive to pain than others and to identify new drugs for treatment of different types of pain. The study involves collecting a standard set of thermal, chemical, inflammatory and mechanical sensitivity measures in groups of mice from 80 different lines in a genetic reference population called the BXD lines.
Data from Lariviere’s study will form an important foundation for integrative genomic analysis of pain. The results will be placed in the public domain through Web resource http://www.genenetwork.org.
“The BXD lines are a powerful tool for integration, but they do not have maximum precision and genetic diversity,” Lariviere said. “For that, we will collect additional trait data in the Collaborative Cross mouse population being created at ORNL.”
One area of specific interest to Lariviere is variations in the amount of messenger RNA (mRNA) produced by different individuals. This often determines how much of a particular protein is made, and that in turn might be related to biological pathways that are involved in processes such as pain perception.
“Because we will measure both the mRNA levels and the sensitivity levels in the same strains of mice, we will be able to efficiently not only study the genes that cause individual differences in pain sensitivity, but also identify the pathway of genes that make ideal targets for new pain drugs,” Lariviere said.
In another study, Michael Miles of Virginia Commonwealth University leads a team that hopes to learn more about the connection between anxiety and alcoholism. Working with Alex Putman and Chesler, the researchers have identified a region of a mouse chromosome that appears to significantly alter the effects of alcohol on anxiety.
“Understanding the basic mechanisms connecting brain events in anxiety and alcoholism could lead to better treatments for both disorders,” Miles said.
In this study, researchers used special strains of mice being raised and maintained at ORNL. Miles noted that the strains of mice used for his study are not available through any commercial source and offer a “great advantage to genetic studies of complex diseases.”
In upcoming months the researchers hope to identify the actual genes in this chromosome region that alter the response to alcohol.
In another study, Bruce O’Hara of the University of Kentucky is working to identify sleep- and wake-related genes. In addition to gaining a more thorough understanding of the sleep process, this research could lead to better drugs to help people with sleep disorders.
O’Hara’s study takes advantage of noninvasive piezoelectric sensors instead of conventional techniques that use electroencephalogram and eletromyogram recordings, which require surgical implants and cables that tether the mouse to a recording device. This limitation has made it impractical to study large numbers of animals, which is necessary in genetic screening, according to O’Hara.
These and other experiments are housed in ORNL’s Laboratory for Comparative Functional Genomics, a pathogen-free 36,000-square-foot facility that is home to approximately 30,000 mice. The lab, completed in 2004, boasts accommodations for 80,000 mice, cryogenic storage and other state-of-the-art features.
UT-Battelle manages Oak Ridge National Laboratory for the Department of Energy. Funding for the mouse facility is provided by DOE’s Office of Biological and Environmental Research within the Office of Science. The Ellison Medical Foundation supports basic biomedical research on aging relevant to understanding aging processes and age-related diseases and disabilities.
Loss is linked to common lung cancer
Little-known bits of RNA help master tumor-suppressor gene do its job, U-M cancer researchers find
Three micro RNA genes appear to be key partners of protective gene p53; their loss is linked to common type of lung cancer
ANN ARBOR, Mich. — Scientists have shown in literally thousands of studies that the p53 gene deserves its reputation as “the guardian of the genome.” It calls to action an army of other genes in the setting of varied cell stresses, permitting repair of damaged DNA or promoting cell death when the cell damage is too great. A key net effect of p53’s action is to prevent development of cancerous cells.
Now, University of Michigan Medical School scientists provide the most thorough evidence yet that p53 also regulates a trio of genes from the realm of so-called “junk” genes — the roughly 97 percent of a cell’s genetic material whose function is only beginning to be understood.
The study shows that “in the ‘junk’ lies treasure, in terms of critical knowledge about how normal cells stifle cancer or succumb to it,” says Guido Bommer, M.D., the lead author of results, published in a recent issue of the journal Current Biology.
“The findings in the study offer new insights into specific mechanisms by which the expression of hundreds to thousands of genes and proteins is altered in the roughly 50 percent of cancers that carry mutations in the p53 tumor suppressor gene,” says Eric Fearon, M.D., Ph.D., senior author of the study and deputy director of the U-M Comprehensive Cancer Center. Scientists continue to mine for details of what goes wrong when p53 is defective and cannot perform its tumor-fighting duties.
The U-M study is one of four recent studies from labs around the world showing that p53 normally gets support from members of a small family of micro RNA genes. The studies are part of a larger effort to understand the function of micro RNA (miRNA for short).
Scientists have long known the importance of messenger RNA (mRNA), which carries protein-making instructions. However, until recently, little was known about micro RNA genes. It is now well recognized that miRNAs regulate the levels of mRNAs, and/or the levels of the proteins produced from mRNAs.
The U-M research team studied the roles of the three genes that make up the miRNA34 family. They showed that the miRNA34 genes work in concert with p53, then went on to explore which other genes the family regulates. They found the miRNA34 genes showed pronounced effects on other genes that control the timing of cell proliferation and division. They also found that the miRNA34 gene family regulated the levels of the Bcl-2 protein, a key factor that enhances a cell’s resistance to death-inducing stimuli.
The team went on to determine if expression of the miRNA34 genes was compromised in human lung cancer cells.
“We found that expression of two of the miRNA34 genes was lost in almost two-thirds of lung adenocarcinomas,” says Bommer.
Adenocarcinomas represent the most common type of non-small cell lung cancer, which is the most frequently diagnosed type of lung cancer. When expression of the miRNA34 genes was restored in lung cancer cells, some of the aberrant growth properties were inhibited.
The discoveries of the role of micro RNAs in tumor suppression could have implications for future cancer therapies.
It’s important to note that micro RNAs alone are not likely to offer new cancer treatment or prevention agents, says Fearon, who is the Emanual N Maisel Professor of Oncology, Professor of Internal Medicine, Professor of Pathology and Professor of Human Genetics at the U-M Medical School.
“However, because of the small size of mature miRNAs, there is optimism that it may be possible to deliver modified nucleic acids that might mimic the effect of the miRNAs,” he says. If modified nucleic acids were to prove effective in more laboratory studies, he adds, they might be pursued further in clinical trials as anti-cancer agents, either alone or more likely in combination with other anti-cancer agents.
In addition to Bommer and Fearon, other U-M authors include: Isabelle Gerin, Ph.D.; Ying Feng, Ph.D.; Andrew J Kaczorowski, B.S.; Rork Kuick, Ph.D.; Robert E Love , B.S.; Yali Zhai, M.D., Ph.D.; Thomas J Giordano, M.D., Ph.D.; Zhaohui S Qin, Ph.D.; Bethany B Moore, Ph.D.; Ormond A MacDougald, Ph.D.; and Kathleen R Cho, M..D., Ph.D.
This research was funded by the National Institutes of Health.
Citation: Current Biology 17, 1298–1307, August 7, 2007
Contact: Anne Rueter
University of Michigan Health System
A promising new line in anti-cancer therapy by blocking the molecular motors involved in copying genetic information during cell division is being pursued by young Dutch researcher Dr. Nynke Dekker in one of this year’s EURYI award winning projects sponsored by the European Science Foundation (ESF) and the European Heads of Research Councils (EuroHORCS). Dekker and her team are trying to stop tumor development by interfering with the molecular motors that copy DNA during cell division. This will cut off the genetic information flow that tumours need to grow, and could complement existing cancer therapies, while in the longer term bringing the promise of improved outcomes with greatly reduced side effects.
There are three primary ways of treating cancer at present, and these have fundamentally changed little in 30 years. In the case of solid tumours, surgery can be used to cut out the cancerous tissue, while radiation therapy can kill the malignant cells, and chemotherapy stops them dividing. Dekker’s work is aiming towards a new generation of drugs that target cancer cells much more specifically than traditional chemotherapy, avoiding side effects such as temporary hair loss.
Dekker is focusing on an enzyme called Topoisomerase IB that plays a key role in some of the molecular motors involved in the processes of DNA and RNA copying during cell division. These are responsible for reading the genetic code and making sure it is encoded correctly in the daughter cell. In healthy cells it is important that this process works normally, but in cancer cells it is a natural target for disruptive therapy. “Specifically targeting these molecular motors in cancer cells would then prevent the cancer cells from growing into a larger tumor,” said Dekker. This molecular copying machinery, constructed mostly out of proteins, in effect walks along the DNA double helix reading the genetic code so that it can be copied accurately into new DNA during division. Other components of the machinery are responsible for slicing and assembling the DNA itself. All of these are potential targets for anti-cancer therapy, providing it is possible to single out the tumor cells. Most existing chemotherapy targets all dividing cells, and the aim to find more sensitive techniques.
However Dekker’s work is not just confined to cancer, having the broader goal within the ESF EURYI project of unraveling the underlying physical principles behind these molecular motors that operate at the nanometer scale to process and manipulate the information stored within the DNA and RNA of our cells. Dekker is exploiting a variety of new highly sensitive manipulation and imaging techniques capable of resolving single molecules. These include force spectroscopy, new forms of optical microscopy with greatly improved resolving power and field depth, as well as nanotechnologies. The research involves cross-disciplinary work among scientists in different fields with the long term goal of developing more precisely targeted molecular medicines for a variety of diseases involving disruption to normal cellular functions and not just cancer.
Dekker’s work has already shown great promise, and she has been able to predict what effect certain antitumor drugs would have on the basis of her molecular insights, confirming her hypotheses in yeast cells. “Indeed the work with antitumor drugs is, as far as I know, the first experiment in which single-molecule experiments have resulted in a prediction for a cellular effect,” said Dekker.
Dekker, a 36-year-old Dutch associate professor at the Technische Universiteit Delft in the Netherlands, is currently undertaking single-molecule studies of DNA and RNA and their interactions with proteins, integrated with nanotechnology where appropriate. She gained her PhD in physics at Harvard University, having graduated from Yale.
As well as being awarded multiple grants and fellowship programmes, Dr. Dekker is a member of the Council of the Biophysical Society, and of the Young Academy of the Royal Academy of Arts and Sciences. She is actively involved in conference organization at the interface of biology and physics. Her group’s research has appeared in Nature and in The Proceedings of the National Academy, USA, among others.
The EURYI awards scheme, entering its fourth and final year, is designed to attract outstanding young scientists from around the world to create their own research teams at European research centres and launch potential world-leading research careers. Most awards are between €1,000,000 and €1,250,000, comparable in size to the Nobel Prize. Dekker will receive his award in Helsinki, Finland on 27 September 2007 with other 19 young researchers.
More on Dekker’s work http://www.esf.org/activities/euryi/awards/2007/nynke-hester-dekker.html
Contact: Thomas Lau
European Science Foundation
- 25-hydroxyvitamin D
- Acetaminophen and Caffeine
- Acinetobacter calcoaceticus-baumannii complex
- acute lymphoblastic leukemia
- American Academy of Neurology
- American Association for Cancer Research
- American Chemical Society
- American College of Cardiology
- American Heart Association
- American Journal of Clinical Nutrition
- American Journal of Public Health
- American Legacy Foundation
- Ancestral Heritage
- Archives of Neurology
- Arthritis & Rheumatism
- Autism Spectrum Disorders
- Autoimmune Diseases
- B. Rappaport Faculty of Medicine at Technion in Haifa
- Biological Sciences
- Blackwell Publishing Ltd.
- Bone Demineralisation
- Bone Diseases
- British Medical Journal
- Brooke Army Medical Center
- Buck Institute
- Calabria Regional Health Department
- Canadian Institutes of Health Research
- Cancer Biology
- Cancer Biology and Therapy
- Cancer Information In Spanish
- Cardiovascular Disease
- Catalan Institute of Oncology in Spain
- Childhood Lukemia
- Childhood Nutrition
- Children's Hospital of Philadelphia
- Children’s Cancer Institute Australia
- Children’s Hospital
- Children’s Hospital of Philadelphia
- Childrens Hospital Los Angeles
- Chromosome 17
- Chromosome 8
- Chronic Multisymptom Illnesses
- Chronic Stress
- Chronic Stress and Obesity
- CHS National Cancer Control Center and Technion
- CHS National Israeli Cancer Control Center
- Clinical Applications
- Clinical Trials
- College of Medicine in Houston
- Complex Chronic Conditions
- Cornell University
- Cytochrome b5
- Cytochrome P450
- Drug Abuse
- Duke University Medical Center
- Electronic Health Records
- Emergency Preparedness
- Emergency Room
- Emory Genetics Laboratory
- Emory University
- End Of Life Care
- European Cancer Conference
- European Journal of Cancer Care
- European League Against Rheumatism
- European Science Foundation
- FDA Warnings
- Fibromyalgia News
- FMS Global News
- Folic Acid
- Fort Sam Houston
- Fox Chase Cancer Center
- Fred Hutchinson Cancer Research Center
- Garvan Institute of Medical Research
- General Psychiatry
- Genetic Link
- Genetic Marker C allele of rs10505477
- Global Health Vision
- Global News
- Health Canada
- Health Information Technology
- Heart Disease
- Hebrew University of Jerusalem
- Hemorrhagic Stroke
- Historical Medicine
- Hospital Epidemiology
- Hospital Trauma
- Howard Hughes Medical Institute
- Human Genome
- Huntington's disease
- Imperial College London
- Interactive Autism Network
- Inuit children
- Irving Weinstein Foundation
- JAMA/Archives journals
- Japanese Society for the Promotion of Science
- Johns Hopkins University
- Joint Health Research Program
- journal BBA Biomembranes
- journal Cell
- journal Nature Genetics
- Journal of Clinical Investigation
- Journal of Experimental Social Psychology
- Journal of the American College of Surgeons
- Journal of Theoretical Biology
- Juvenile Diabetes
- Karolinska Institute in Stockholm
- Kennedy Krieger Institute
- Kyowakai Hospital
- Lamezia Terme
- London UK Feed
- Lung Cancer
- Massachusetts General Hospital
- Mayo Clinic
- McMaster University
- Medical History
- Medical Insurance
- Medical Journals
- Mitochondrial Diseases
- Molecular Biology
- Molecular Epidemiology
- Multiple Sclerosis
- Muscular Dystrophy
- Music Video Of The Day
- Music Video Pick Of The Day
- National Cancer Institute
- National Institute on Aging
- National Institutes of Health
- Nature Genetics
- Neurodegenerative Diseases
- Neuropeptide Y
- New England Journal of Medicine
- New York University
- News Australia
- News Canada
- News France
- News Germany
- News Israel
- News Italy
- News Jerusalem
- News Switzerland
- News UK
- News US
- News USA
- non-Hodgkin's lymphoma
- Northwestern University
- Nova Scotia
- Nutritional Anthropology
- Oak Ridge National Laboratory
- Occupational Health
- omega-3 fatty acids
- Orthopaedic Research Society
- Ottawa City Feed
- Oxford University
- Pain Management
- Palliative Care
- Parkinson Society of Canada
- Pediatric Palliative Care
- Peutz-Jeghers syndrome
- Pharmacology and Neuroscience
- Pick's Disease
- Pre/Post Natal Care
- Preventive Medicine
- Prince Edward Island
- Protein Growth Factor
- Public Health
- Research Australia
- Rheumatoid Arthritis
- RSS Feed
- Rush Alzheimer’s Disease Center
- Seattle Washington
- Spina Bifida
- Spinal Cord Injuries
- St. Elmos Fire
- St. Jude Children's Research Hospital
- Statin Drugs
- Stem Cells
- Sydney Children’s Hospital
- Systemic Lupus Erythematosus
- Temple University
- The American Academy of Neurology
- the Israel Institute of Technology
- Toronto City Feed
- trauma-associated and hospital-acquired infection
- Type 1 Diabetes
- Type 2 Diabetes
- Université Laval
- University College London
- University Hospital in Geneva
- University New South Wales
- University of Bern
- University of Calgary
- University of California
- University of Chicago
- University of Chicago Press Journals
- University of Florida
- University of Granada
- University of Manchester
- University of Michigan
- University of Missouri
- University of North Carolina
- University of North Texas
- University of Nottingham
- University of Oregon
- University of Pennsylvania School of Medicine
- University of Pittsburgh
- University of Rochester
- University of Toronto
- US Army soldiers in Iraq
- US Military Hospitals
- UT Southwestern Medical Center
- Vitamin D
- W. Garfield Weston Fellows
- Wake Forest University Baptist Medical Center
- Washington DC
- Washington DC City Feed
- Washington University
- Weather Anomolies
- Weill Medical College
- Wellcome Trust
- World Health Organisation
- World News
- Yale University