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.
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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
Scientists have only recently begun to speculate that what’s referred to as “junk” DNA – the 96 percent of the human genome that doesn’t encode for proteins and previously seemed to have no useful purpose – is present in the genome for an important reason. But it wasn’t clear what the reason was. Now, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered one important function of so-called junk DNA.
Genes, which make up about four percent of the genome, encode for proteins, “the building blocks of life.” An international collaboration of scientists led by Michael G. Rosenfeld, M.D., Howard Hughes Medical Investigator and UCSD professor of medicine, found that some of the remaining 96 percent of genomic material might be important in the formation of boundaries that help properly organize these building blocks. Their work will be published in the July 13 issue of the journal Science.
“Some of the ‘junk’ DNA might be considered ‘punctuation marks’ – commas and periods that help make sense of the coding portion of the genome,” said first author Victoria Lunyak, Ph.D., assistant research scientist at UCSD.
In mice, as in humans, only about 4 percent of the genome encodes for protein function; the remainder, or “junk” DNA, represents repetitive and non-coding sequences. The research team studied a repeated genomic sequence called SINE B2, which is located on the growth hormone gene locus, the gene related to the aging process and longevity. The scientists were surprised to find that SINE B2 sequence is critical to formation of the functional domain boundaries for this locus.
Functional domains are stretches of DNA within the genome that contain all the regulatory signals and other information necessary to activate or repress a particular gene. Each domain is an entity unto itself that is defined, or bracketed, by a boundary, much as words in a sentence are bracketed by punctuation marks. The researchers’ data suggest that repeated genomic sequences might be a widely used strategy used in mammals to organize functional domains.
“Without boundary elements, the coding portion of the genome is like a long, run-on sequence of words without punctuation,” said Rosenfeld.
Decoding the information written in “junk” DNA could open new areas of medical research, particularly in the area of gene therapy. Scientists may find that transferring encoding genes into a patient, without also transferring the surrounding genomic sequences which give structure or meaning to these genes, would render gene therapy ineffective.
Contributors to the paper include Lluis Montoliu, Rosa Roy and Angel Garcia-Díaz of the Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología in Madrid, Spain; Christopher K. Glass, M.D., Ph.D., UCSD Department of Cellular and Molecular Medicine; Esperanza Núñez, Gratien G. Prefontaine, Bong-Gun Ju, Kenneth A. Ohgi, Kasey Hutt, Xiaoyan Zhu and Yun Yung, Howard Hughes Medical Institute, Department of Molecular Medicine, UCSD School of Medicine; and Thorsten Cramer, Division of Endocrinology, UCSD Department of Medicine.
The research was funded in part by the Howard Hughes Medical Institute and the National Institutes of Health.
Contact: Debra Kain
University of California – San Diego
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