Research Team Identifies New Alzheimer's Gene

Research Team Identifies New Alzheimer’s Gene

Source: TGen

A study comparing more genetic markers in the DNA of people with and without Alzheimer’s disease than ever before has enabled researchers to identify a common gene that appears to increase a person's risk for developing Alzheimer's disease. The finding, announced today by researchers at the Translational Genomics Research Institute (TGen), Banner Alzheimer's Institute, Kronos Science Laboratory and their collaborative partners, suggests that the gene - called GAB2 - modifies an individual's risk when associated with other genes, including APOE4. The study results appear in the June 7 issue of the prestigious peer-reviewed journal, Neuron.

Alzheimer's disease is the most common form of disabling memory and thinking problems in older people. The progressive neurological disorder afflicts an estimated 5 million Americans, a number expected to triple by 2050. "We have entered a new era in medical research. Today's technologies permit us to survey a sufficient number of letters throughout the human genome to provide a clearer picture of how life works and ultimately allow better clinical management of patients," said Dr. Dietrich Stephan, Director of TGen's Neurogenomics Division and the paper's senior author, "These new, robust tools may eventually allow us to improve our ability to diagnose Alzheimer's disease, even before it strikes."

To date, the most significant gene found to predispose an individual to late onset Alzheimer's (LOAD) has been APOE4. In this latest study, researchers from seven organizations contributed to the genome-wide scan using Affymetrix microarray technology. The team screened the DNA from 1,400 individuals who had been clinically assessed with Alzheimer's prior death, and simultaneously examined more than 500,000 SNPs or genetic variations to characterize and confirm additional LOAD susceptibility genes. The search revealed GAB2.

Based on the genetics of this and other neuroscientific findings, researchers suggest the healthy form of the GAB2 gene may protect brain cells from developing tangles, one of the hallmarks of Alzheimer's disease. If the findings are confirmed, this discovery could provide a target for future Alzheimer's therapeutic drugs. "We hope that this study, along with the genome-wide genetics studies to come, will contribute to the clarification of Alzheimer's risk factors and disease mechanisms, the discovery of promising new disease-slowing and prevention therapies, and the identification of patients and at-risk people most likely to benefit from those treatments," said Dr. Eric Reiman, the study's first author and Executive Director of the Banner Alzheimer's Institute.

After finding an association between a form of the GAB2 gene and Alzheimer's disease in three separate groups, the researchers showed that the GAB2 gene is unusually active in vulnerable brain cells from Alzheimer's patients and that the GAB2 protein produced by this gene is present in those brain cells containing tangles. When the researchers silenced GAB2 in preliminary studies it increased a molecular process thought to play an important role in the development of tangles. Based on these findings, the researchers hypothesize that GAB2 might function under normal conditions to compensate for the harmful effects of APOE4 and other genes in older people and that the GAB2 risk gene lacks this protective effect.

The study, funded by Kronos Science Laboratory, an affiliate of Phoenix-based Kronos Optimal Health Company, will enable Kronos to develop a test that aids in clinical diagnosis and help determine a person's genetic predisposition for developing Alzheimer’s disease. "This discovery allows us to accelerate the development process for creating a new diagnostic test that is capable of detecting the presence of GAB2, and may ultimately help millions of individuals reach a more informed decision regarding the most appropriate type and timing of treatment," said Dr. Chris Heward, President of Kronos Science Laboratory.

Until recently, researchers lacked the technology to examine the genetic components of a disease at such a high-level of detail. By utilizing the Affymetrix 500K Arrays, the study's researchers rapidly produced a genetic map of each brain tissue sample and isolated the GAB2 gene relatively quickly. "This Alzheimer's disease breakthrough is another powerful example of a fundamental life science discovery made by an Affymetrix customer. Our latest microarray technology continues to accelerate research at an unprecedented pace by enabling scientists to better identify the specific genetic variations associated with complex diseases," said Kevin King, President of Life Sciences Business and Executive Vice President at Affymetrix.

In addition to surveying an unprecedented number of genetic markers in each person's DNA, the researchers capitalized on extremely rigorous criteria to determine whether or not their volunteers had Alzheimer's. For instance, the study included more than 1000 brain donors confirmed to either have Alzheimer's disease or be free of the disorder at autopsy. This study resulted in a comprehensive set of high-quality data to be made publicly available to the research community. The researchers believe that deposition of this data set in the public domain will open a new era in Alzheimer research. When a scientist suspects a particular gene or pathway maybe implicated in Alzheimer's disease, they will use these data to see if there is genetic evidence supporting their idea. Reviewing these data in an hour will permit them to save months of work and thousands of dollars to achieve the same result. Moreover, it paves the way for even more advanced studies using larger sample populations, more powerful array chips that can distinguish more genetic markers, and more sophisticated methods of analyzing the data.

Study participants included TGen, Kronos Science Laboratory, Banner Alzheimer's Institute, Mayo Clinic Scottsdale, the Netherlands Brain Bank, Sun Health Research Institute, the University of Arizona, Arizona State University, the Arizona Alzheimer's Consortium, and several Alzheimer's Disease Centers supported by the National Institutes of Health's National Institute of Aging.

TGen study identifying alteration in gene associated with uterine cancer lays groundwork for more targeted therapies

Researchers at the Translational Genomics Research Institute announced the discovery of previously unrecognized alterations in a gene called FGFR2 in a subset of endometrial cancers, the most common gynecologic cancer in the United States. The mutations in FGFR2 result in uncontrolled cell division, a hallmark of cancer. The findings, reported by TGen and research colleagues at Washington University School of Medicine in St. Louis, the Wellcome Trust Sanger Institute, which is part of Cambridge University, and New York University School of Medicine, could accelerate the development of new treatments for endometrial cancer because there are drugs already in clinical trials that inhibit FGFR2 function. The study appears in the May 21, 2007 online version of the journal Oncogene.

Nearly 40,000 women are diagnosed with endometrial cancer each year, making it the fourth most common cancer found in women, following breast cancer, lung cancer and colon cancer. Endometrial cancer usually begins in the lining of the uterus and is most commonly found in women between the ages of 60 and 70. If discovered early, this slow-growing cancer can be successfully treated by surgical removal of the uterus. However, about 7,000 women die each year from the more aggressive form of endometrial cancer.

Researchers at TGen used the latest genome-scanning technology to sequence 187 endometrial tumor samples. The research team identified mutations in FGFR2 in 16% of tumors that represented a specific subset of endometrial cancer. The other types of endometrial cancer did not have these mutations. The FGFR2 gene encodes a protein that plays a critical role in cell growth. In patients with FGFR2 mutations, the tumors were caused by the receptor for this protein being permanently stuck in the "on" position.

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Mayo Clinic - Spread of breast cancer to lungs in asthma patients may be prevented by use of common inhalers

Researchers at Mayo Clinic in Arizona suggest there may be a link between asthma and the spread of cancer in breast cancer patients. Importantly, using available inhaler medications could reduce potential metastasis to the lungs in breast cancer patients who have asthma. The study was conducted in mice and supported by examination of breast cancer patient records. The results, according to the researchers, offer a biological link: Activation of cells that line blood vessels is required for the movement of pro-inflammatory white blood cells (which occurs in asthma) and for the movement of circulating cancer cells from the blood into lung tissue.

In the study, mice that were exposed to an allergen commonly used in mouse asthma studies and then injected with melanoma cells were compared to control groups of mice that did not suffer from allergic asthma. The allergen-induced pulmonary inflammation in the asthmatic mice was associated with an almost 400 percent increase in lung metastasis in these animals. But in mice treated with a medication currently available to asthma patients that reduces their lung inflammation (corticosteroids self-administered using hand-held inhalers), the rate of metastasis fell to that seen in mice that were not exposed to an allergen.

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Alliance Aims to Boost Biomedicine

Arizona’s bioscience efforts continue to grow through an extensive, statewide collaborative network of initiatives. Now, research capabilities are being allied around the state in a new effort to improve medical diagnostics and human health.

The Arizona Proteomics Alliance (AZPA), a statewide consortium, has been formed to advance the emergent science of proteomics, a science whose broad vision is to understand the biological role of the complete set of proteins in the human body, or proteome. The initiative combines the expertise of nine leading Arizona institutions, including ASU, Banner Health, Barrow Neurological Institute, Carl T. Hayden Veterans Affairs Medical Center, Intrinsic Bioprobes Inc., Mayo Clinic, Sun Health Research Institute, Translational Genomics Research Institute (TGen) and the University of Arizona (U of A). “This alliance places Arizona in the forefront of proteomics research capabilities and will no doubt have broad impact on biomedical research and personalized medicine,” said Jeff Trent, president and scientific director of TGen.
AZPA promotes a team approach to solving problems of significant biomedical interest, according to Michael Mobley, administrative director of AZPA and associate director of the Biodesign Institute at ASU. The alliance will advance the role of proteomics research in the understanding of human health and disease by creating a network of scientists who share resources and expertise.

“AZPA facilitates access to technical and intellectual resources that are rarely surpassed within the United States, and provides the state with a distinct competitive advantage in this field,” says Serrine Lau, scientific director of AZPA, director of Southwest Environmental Health Sciences Center at the U of A’s College of Pharmacy, and a member of U of A’s BIO5 Institute. “We are pleased that the resources of the Arizona Proteomics Consortium at U of A will be part of this state-wide alliance,” Lau says.

The Mayo Clinic is also expecting to be able to expand its efforts and bring new diagnostic and treatment options to its patients as part of the proteomics initiative, according to Laurence Miller, director of research and the cancer center at the Arizona Mayo Clinic. “The alliance will put Arizona in a stronger position to compete for federal and private research funding,” Mobley says.

The effort builds on the vast knowledge generated by the Human Genome Project, which has mapped roughly 25,000 genes. Each gene codes for the production of protein, but with all the modifications possible to both the gene transcript and protein, the human body could have well over a million different proteins, according to the Human Proteome Initiative. This entourage of proteins, the proteome, is ultimately responsible for everything, good or bad, related to human health and disease. Developing tests to rapidly obtain protein profiles as a predictive marker for disease or identifying therapeutic targets benefit health care and medicine.

Leslie Tolbert, vice president for research, graduate studies and economic development at U of A, said that the pooling of technologies statewide would allow researchers to maximize capabilities and minimize costs in a field that requires the development of new research methods. For example, this collaborative effort is expected to foster an expansion of the cancer research initiative at Banner Health, the state’s largest hospital system, says Susan Edwards, president of the Arizona region for Banner Health. A unifying research approach within the alliance is “integrative proteomics,” which involves advancing the processes, methods and technologies that elucidate the role of proteins within an integrated understanding of human biology, according to Mark Hayes, director of Arizona Applied NanoSensors in the College of Liberal Arts and Sciences at ASU. “This means developing proteomics research capabilities so that they are complementary to other advancing fields like genomics, bioinformatics and clinical research,” says Hayes, who was an early champion for the expansion of regional proteomics and the formation of this alliance.

The alliance has just launched a Web site (http://www.integrativeproteomics.org/) where researchers can exchange information about resources and the important problems they are working together to solve. “Collaboration is one of the things that sets Arizona science apart from other states, where competition is more often the rule,” says Joseph Rogers, president and senior scientist of the Sun Health Research Institute. The important partnerships formed in proteomics are expected to not only expand research efforts and improve chances for greater funding, but also to promote the future recruitment and training of talented individuals for the field of health care in Arizona.

Detecting and identifying contamination from bacteria, viruses, and other microbes at UA

Self-decontaminating surfaces and inexpensive devices that can be used anywhere to rapidly diagnose disease are two areas of research for new BIO5 member Linda S. Powers, PhD. The projects are part of her interest in developing technology to detect and identify contamination from bacteria, viruses and other microbes. Microbe detection is accomplished with light (the intrinsic florescence of the microbes) and the detection instrument is very sensitive and measures small numbers of microbes in real time. Once the microbe is detected, a second test (small molecules that binds to specific microbes) reveals what it is within a few seconds.

Dr. Powers joined The University of Arizona (UA) faculty this year, coming from Utah State University. Also moving to Tucson this year is the company Dr. Powers founded, MicroBioSystems, which manufactures and licenses the detection and identification of microbes. The company builds and tests prototypes for other companies, and licenses the technology. Dr. Powers is a professor of electrical and computer engineering and the Thomas R. Brown Chair of Bioengineering, and director of the National Center for the Design of Molecular Function at the UA.

Dr. Powers is joined by BIO5 member Walther R. Ellis, Jr., PhD, who also relocated to the UA from Utah State University. He is a research professor of Chemical and Environmental Engineering and associate director of the National Center for the Design of Molecular Function.

BNI's Dr. Pipe to serve on International Society for Magnetic Resonance in Medicine Board of Trustees

Jim Pipe, Ph.D., of the Barrow Neurological Institute and St. Joseph’s Hospital, was recently elected to serve on the Board of Trustees of the International Society for Magnetic Resonance in Medicine (ISMRM). The ISMRM is the premier international society for research, development, and applications in the field of magnetic resonance in medicine and biology and other related topics. Its multidisciplinary membership of over 5,000 members and consists of clinicians, physicists, engineers, biochemists, and technologists. Each year the ISMRM elects four new members to the board, a scientist and a clinician from both inside and outside of North America. Dr. Pipe was elected by his peers as the North American scientist from a slate of four candidates, and will serve a 3-year term starting in May 2007.

According to ASU, there's a new wrinkle in evolution -- man-made proteins

Nature, through the trial and error of evolution, has discovered a vast diversity of life from what can only presumed to have been a primordial pool of building blocks. Inspired by this success, a new Biodesign Institute research team, led by John Chaput, is now trying to mimic the process of Darwinian evolution in the laboratory by evolving new proteins from scratch. Using new tricks of molecular biology, Chaput and co-workers have evolved several new proteins in a fraction of the 3 billion years it took nature. Their most recent results, published in the May 23rd edition of the journal PLoS ONE, have led to some surprisingly new lessons on how to optimize proteins which have never existed in nature before, in a process they call ‘synthetic evolution.’

"The goal of our research is to understand certain fundamental questions regarding the origin and evolution of proteins," said Chaput, a researcher in the institute’s Center for BioOptical Nanotechnology and assistant professor in Arizona State University’s department of chemistry and biochemistry. "Would proteins that we evolve in the lab look like proteins we see today in nature or do they look totally different from the set of proteins nature ultimately chose" By gaining a better understanding of these questions, we hope to one day create new tailor-made catalysts that can be used as therapeutics in molecular medicine or biocatalysts in biotechnology."

The building blocks of proteins are 20 different amino acids that are strung together and folded to make the unique globular shape, stability and function of every protein. The mixing and matching of the amino acid chain like numbers in the lottery are what favor the odds in nature of finding just the right combinations to help generate biological diversity. Yet no one can predict how the string of amino acids sequence folds to make the 3-D functional structure of a protein.

John Chaput, a researcher at the Biodesign Institute at Arizona State University, has used molecular biology tricks to rapidly evolve proteins that have improved stability when compared to naturally occuring... To select the raw ingredients to create the proteins, Chaput’s group (which includes Harvard collaborator Jack Szostak, and ASU colleagues Jim Allen, Meitian Wang, Matthew Rosenow and Matthew Smith) began their quest by further evolving a protein that had been previously selected from a pool of random sequences.

Jack Szostak and Anthony Keefe first made the parental protein in 2001. To achieve their feat, they stacked the odds of finding just one or two new proteins and generated a library of random amino acid sequences so vast — 400 trillion — that it dwarfs the number of items in the entire Library of Congress (134 million). They started with a small protein stretch 80 amino acids long. This basic protein segment acts as a protein scaffold that can be selected for the ability to strongly clutch its target molecule, ATP. There was only one problem, the parental protein could bind ATP, but it wasn’t very stable without it. "It turns out that protein stability is a major problem in biology," said Chaput. "As many as half of the 30,000 genes discovered from the human genome project contain proteins that we really don’t know what their structure is or whether or not they would be stable. So for our goal, we wanted to learn more about the evolution of protein folding and stability."

Chaput’s group decided to speed up protein evolution once again by randomly mutating the parental sequence with a selection specically designed to improve protein stability. The team upped the ante and added increasing amounts of a salt, guanidine hydrochloride, making it harder for the protein fragment to bind its target (only the top 10 percent of strongest ATP binders remained). After subjecting the protein fragments to several rounds of this selective environmental pressure, only the ‘survival of the fittest’ ATP binding protein fragments remained. The remaining fragments were identified and amino acid sequences compared with one another. Surprisingly, Chaput had bested nature’s designs, as the test tube derived protein was not only stable, but could bind ATP twice as tight as anything nature had come up with before. To understand how this information is encoded in a protein sequence, Chaput and colleagues solved the 3-D crystal structures for their evolutionary optimized protein, termed DX, and the parent sequence.

In a surprising result, just two amino acids changes in the protein sequence were found to enhance the binding, solubility and heat stability. "We were shocked, because when we compared the crystal structures of the parent sequence to the DX sequence, we didn’t see any significant changes," said Chaput. "Yet no one could have predicted that these two amino acids changes would improve the function of the DX protein compared to the parent. The results have helped provide a new understanding of how subtle amino acid changes contribute to the protein folding and stability. Chaput’s team has developed the technology potential to take any of nature’s proteins and further improve its stability and function. "We have the distinct advantage over nature of being able to freeze the evolution of our lab-evolved proteins at different time points to begin to tease apart this random process and relate it to the final protein function," said Chaput. Next, Chaput plans on further expanding his efforts to evolve proteins with new therapeutic features or catalytic functions.

For more information, contact Joe Caspermeyer, joseph.caspermeyer@asu.edu, 480-727-0369