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Huntington’s disease study shows animal models on target

This release is available in French.

An international team of researchers has published a benchmark study showing that gene expression in several animal models of Huntington’s Disease (HD) closely resembles that of human HD patients.

The results, published August 1, 2007, in the , validate the applicability of using animal models to study human disease and will have important consequences for the pertinence of these models in preclinical drug testing.

Huntington’s disease is an incurable and fatal hereditary neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to severe motor, psychiatric, and cognitive decline. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This disease mechanism is a promising new avenue for research into the causes of neuronal death and a novel potential approach for treatment.

Led by EPFL professor Ruth Luthi-Carter, and involving collaborators from six countries, the current study found a marked resemblance between the molecular etiology of neurons in animal models and neurons in patients with HD. This implies that animal models are relevant for studying human HD and testing potential treatments.

To come to this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons. They then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients. “Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD,” explains Luthi-Carter. “It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington’s Disease.”

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More Information:

EPFL Laboratory of functional neurogenomics, http://lngf.epfl.ch/

Alexandre Kuhn ; +41 21 693 1731
alexandre.kuhn@epfl.ch

Professor Ruth Luthi-Carter; +41 21 693 9533
ruth.luthi-carter@epfl.ch

Contact: Alexandre Kuhn
alexandre.kuhn@epfl.ch
41-216-931-731
Ecole Polytechnique Fédérale de Lausanne

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July 31, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Calgary, Canada, DNA, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Human Genome, Huntington's disease, Italy, Japan, Neurodegenerative Diseases, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, Nova Scotia, Nunavut, Ottawa, Prince Edward Island, Proteins, Quebec, Research, RSS, RSS Feed, Spain, Toronto, UK, US, Virginia, Washington DC, Washington DC City Feed, World News | Leave a comment

One man’s junk may be a genomic treasure

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
ddkain@ucsd.edu
619-543-6163
University of California – San Diego

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July 13, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Chile, DNA, Genes, Genetic, Genetics, Genome, Genomic, Global, Global Health Vision, Global News, Howard Hughes Medical Institute, Human Genome, Irvine, Italy, Japan, National Institutes of Health, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nova Scotia, Osaka, Ottawa, Pennsylvania, Prince Edward Island, Proteins, Quebec, Research, Research Australia, RSS, RSS Feed, Slovakia, Spain, Toronto, UCSD, University of California, Virginia, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

Researchers Create Model of Cancer-Preventing Enzyme, Study How It Works

May 11 2007

Contact: Katherine Kostiuk
Sr. Information Specialist
573-882-3346
KostiukK@missouri.edu

Proline dehydrogenase is important because it plays a role in apoptosis, the process of cell death, by enabling the creation of superoxide, a highly reactive electron-rich oxygen species. Superoxide is involved in the destruction of damaged cells and therefore is important in preventing the development and spread of cancer. The protein proline dehydrogenase “opens up to allow oxygen to ‘steal’ electrons” and create a superoxide, said Tommi A. White, an MU doctoral student in biochemistry.

White worked with John J. Tanner, professor of chemistry and biochemistry in MU’s College of Arts and Science, and Navasona Krishnan, a doctoral student at the Unviersity of Nebraska-Lincoln, and Donald F. Becker, an associate professor at the University of Nebraska-Lincoln, to create the first model of proline dehydrogenase. Because the human form of this enzyme is difficult to work with, the team studied proline dehydrogenase from the bacteria Thermus thermophilus. They used bioinformatics and biochemical studies to show that this enzyme is functionally similar to the human version, so their results can be generalized to the human version, as well as the bacterial version.

Using X-ray crystallography and biochemical analysis, the team created a model of proline dehydrogenase that can tell scientists more about the molecule’s structure and functions.

“The three-dimensional model tells us a lot about the structure of the molecules and helps us understand how they work,” Tanner said. “This protein is important in cancer prevention because it enables the creation of superoxide, which aid in cell death. Cells aren’t meant to live forever, and at some point, they need to die and be destroyed. Cells that are damaged or diseased are usually destroyed in this process. Our structure tells us how oxygen gets access to electrons stored in the enzyme. We think we’ve identified a gate that opens to let oxygen into the enzyme where the electrons are stored.”

In this way, proline dehydrogenase is important in preventing cancer. White said it’s unusual for proline dehydrogenase to be involved in such a process because the usual job of this type of enzyme is to transfer electrons to the mitochondrial membrane, not allow them to be attached to oxygen to create highly reactive superoxides.

Tanner and White said they hope to continue to study proline dehydrogenase and the molecules that can inactivate it. They also plan to examine another protein they suspect works in collaboration with proline dehydrogenase to understand how that protein affects the cancer-preventing abilities of proline dehydrogenase.
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On the Net:
University of Missouri
http://www.chem.missouri.edu/

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May 11, 2007 Posted by | Cancer, Clinical Trials, DNA, Enzymes, Genetics, Global, Global Health Vision, Global News, Human Genome, News, Uncategorized, University of Missouri, Washington DC | Leave a comment

Study finds regions of DNA that appear linked to autistic spectrum disorders

Contact: Jim Dryden
jdryden@wustl.edu
314-286-0110
Washington University School of Medicine

Using an innovative statistical approach, a research team from Washington University School of Medicine in St. Louis and the University of California, Los Angeles, has identified two regions of DNA linked to autism. They found the suspicious DNA with a much smaller sample of people than has been used traditionally in searches for autism genes.

Autism — a disorder that involves social deficits, language problems and repetitive, stereotyped behaviors — affects around one in 1,000 children. And the combined incidence of autism spectrum disorders, which include Asperger syndrome and pervasive developmental disorder, brings the total number of affected children to one in every 150 births. Boys are affected three to four times more often than girls.

There’s clearly a genetic component to autism, according to John N. Constantino, M.D., associate professor of psychiatry and pediatrics at Washington University School of Medicine and a co-principal investigator on this latest study. If one child in a family is autistic, there’s a 10 percent chance a sibling also will have autism. Past research has isolated a few regions of DNA linked to autism, but very few of those studies have been replicated, so no specific autism genes have yet been identified.

“Those older studies used what’s called an ‘affected sib pair’ design that looks for genetic markers in siblings with autism,” says Constantino. “That approach has worked well for single-gene disorders, but autism is a complex disease that may involve many genes that each make very small contributions. When that’s the case, it’s harder to find genetic markers.”

So Constantino’s group, in collaboration with the other co-principal investigator, Daniel H. Geschwind, M.D., Ph.D., and neuropsychiatric and genetics researchers at UCLA, is using a different approach. They report their findings in the April issue of the American Journal of Psychiatry.

“Although we once believed you either had this condition or you didn’t, we now know that there’s a continuous distribution of autism symptoms from very mild to very severe,” Constantino says.

That means in families where a child is autistic, parents and unaffected siblings may have very subtle communication impairments or behavioral tendencies that would be considered autistic only in their most severe forms. Those traits may indicate genetic tendencies that contribute to autism and now can be measured with a diagnostic interview tool called the Social Responsiveness Scale (SRS), which Constantino developed with his colleague Richard D. Todd, Ph.D., M.D., at Washington University.

Using the SRS to gather data about both children with autism and their unaffected parents and siblings allowed the researchers to take a more quantitative approach to find subtle symptoms of autism that aggregate in families. In all, they used the SRS to study members of 99 families who were part of the Autism Genetic Resource Exchange (AGRE).

“We characterized everyone using the quantitative measures that the Social Responsiveness Scale provides,” Constantino explains. “With the SRS, we looked not just at whether a person has autism but more systematically at the degree of autistic impairment. Then we analyzed their genetic material and found significant linkage to these symptoms on regions of chromosomes 11 and 17.”

Older survey methods also had flagged those regions of DNA, but those studies used samples more than three times larger than this study. Constantino and Geschwind believe the fact that they identified the same areas of DNA means that their quantitative method can find genes related to autism and that if used in bigger samples, it may be able isolate other suspicious regions of DNA that studies using traditional methods can’t find.

The researchers now have begun to make more detailed maps of the chromosome regions related to autism. They’re also using the SRS to study more families.

In theory, the greater statistical power of their method will be magnified as the researchers study larger numbers of people. They say that power may help them isolate many more genes that might contribute to autism spectrum disorders. They’ll also continue to look closely at genes in the suspicious DNA regions identified so far and try to figure out what’s going on at the genetic level to make some children autistic.

“We know that the dopamine D4 receptor gene is in the region we’ve identified on chromosome 11,” Constantino says. “That receptor is important in many brain functions. But there are many genes in the regions we’ve identified, and our focus is on refining the signal so that we can reduce the number of candidate genes and then look more closely at how those genes might be contributing to this devastating disorder.”

Constantino believes ultimately the search will lead to the discovery of many genes that contribute to autism and that scientists may need to find several of them before they begin to understand how genetic variations actually lead to the disorder.

“The genetic factors tend to interact with one another,” he says. “One gene might increase risk by 10 percent, but two genes, in the proper combination, might increase the risk 10-fold. We expect that as we find additional susceptibility factors the amount of their causal influence will increase exponentially, and we’ll get a clearer picture of how genes contribute to autism and may even find ways to intervene.”

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The Autism Genetic Resource Exchange (AGRE) is a collaborative gene bank designed to speed to pace of research to find the genes and ultimately the cure for autism. AGRE was established by the non-profit foundation Cure Autism Now.

For more information about autism studies at Washington University, please call Teddi Gray, research coordinator for the Social Developmental Studies program at (314) 286-0068.

Duvall JA, Lu A, Cantor RM, Todd RD, Constantino JN, Geschwind DH. A quantitative trait locus analysis of social responsiveness in multiplex autism families. American Journal of Psychiatry, vol. 164:4, pp. 656-662 April 2007

This research was supported by the National Institutes of Health and Cure Autism Now.

Related papers

Constantino JN, Todd RD. Intergenerational transmission of subthreshold autistic traits in the general population. Biological Psychiatry, vol. 57:6, pp. 655-660, March 15, 2005.

Constantino JN, Todd RD. Autistic traits in the general population. Archives of General Psychiatry, vol. 60:6, pp. 524-530, May 2003.

Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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May 9, 2007 Posted by | Autism, DNA, Genetics, Global, Global Health Vision, Global News, Washington University | Leave a comment