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March 19, 2009


Protein’s structure impacts Huntingdon’s

In a paper published in the early online version of Nature Structural & Molecular Biology, researchers at the School of Medicine deconstruct the first steps in an intricate molecular dance that might lead to the formation of pathogenic protein clumps in Huntington’s disease, and possibly other movement-related neurological disorders.

Huntington’s disease is an inherited disease in which progressive degeneration of certain brain neurons causes uncontrolled writhing, twisting and jerking movements, and cognitive and psychiatric problems.

Huntington’s is one of 10 diseases in which a certain protein, different for each disease, contains polyglutamine, a stretch of repeating blocks of the amino acid glutamine, explained Ronald Wetzel, professor of structural biology and member of the Pittsburgh Institute for Neurodegenerative Diseases at the School of Medicine. The affected protein in Huntington’s disease is called huntingtin.

Most people have a huntingtin protein whose polyglutamine segment contains 20 or so glutamines, and even a polyglutamine with as many as 35 repeats may not cause Huntington’s symptoms. But the risk of developing Huntington’s disease rises sharply in individuals whose polyglutamine sequences are only slightly larger. A block of 40 repeats, for example, is associated with a very high likelihood of having the disease.

“To a protein chemist, this is a fascinating situation,” Wetzel said. “Polyglutamine doesn’t seem to play a sophisticated role in these proteins, and it doesn’t have a defined structure. Yet by changing its length to only a very slight extent, it takes on some new physical properties that somehow initiate diseases.”

One consequence of the lengthening is protein aggregation, or clumping, a feature that consistently appears in brain cells of patients who have one of these neurodegenerative diseases. Many research groups, including Wetzel’s, study how polyglutamine expansion alters the huntingtin protein’s behavior.

In its most recent studies, the Pitt team worked out the details of how the aggregation behavior of huntingtin depends, in a surprisingly intricate way, on the neighboring segments of amino acid sequence flanking the polyglutamine. They found that longer polyglutamine sequences have the ability to disrupt the structure of a neighboring region, 17 amino acids long, at the beginning of the protein known as the N-terminus. That sets the stage for new physical interactions with the rest of the huntingtin protein that drive it to aggregate.

“If the N-terminus is not there, huntingtin makes clumps very slowly, even if the polyglutamine stretch is rather long,” Wetzel noted. “When the N-terminus is disrupted by its polyglutamine neighbor, it takes a lead role in the aggregation process, with the polyglutamine then following to consolidate and stabilize the clumps — a kind of ‘aggregation two-step.’”

The choreography might be similar in other polyglutamine diseases, meaning physical disruption of neighboring regions may influence the tendency for the protein to clump, he added.

The research was funded by the National Institutes of Health (NIH), the Huntington’s Disease Society of America, the National Science Foundation (NSF), Petroleum Research Fund/American Chemical Society and the Commonwealth of Pennsylvania.


OOR announces funding

The Office of Research recently announced the following new and continuing grants to Pitt faculty:

• Neurology professor Oscar Lopez received a continuation grant of $2.9 million from NIH for a study to determine whether gingko biloba can impact dementia and Alzheimer’s disease in older individuals.

• Peter Wipf of chemistry was awarded an NIH renewal grant of $1.67 million for his project, “New Concepts, Methodologies and Scaffolds for Diversity Oriented Organic Synthesis.” The project is focused on the development of a multi-investigator research center whose mission is to develop efficient, general state of the art methodologies for the design, synthesis, analysis and handling of chemical diversity libraries.

• Julie Fiez of psychology was awarded $1.2 million from NSF for “Training of Arithmetical Fluency.” The project aims to determine whether a new training approach based on neuroscience knowledge improves the ability to solve multi-digit addition and subtraction problems and to determine whether the benefits extend to other types of mathematical tasks, such as solving algebra problems. The study includes measures of brain function to test the idea that the approach leads to adaptive changes in a core brain region involved in basic number sense.

• Paul Pilkonis of WPIC was awarded a continuation grant of nearly $1.2 million from NIH for a research project that seeks to better establish the magnitude of relationships between psychiatric symptoms such as depression, anxiety, anger, hostility and alcohol and substance abuse and social functioning.

• Matthew Freiberg of medicine was awarded an NIH grant of $978,000 for “Cardiovascular Disease Mechanisms in HIV Infected and Uninfected Veterans.” The project aims to improve understanding of cardiovascular disease risk among people infected with HIV.

• Thomas Kleyman of medicine was awarded $799,000 from NIH for the Pittsburgh Center for Kidney Research. The center’s objective is to reinforce and expand interactions among investigators at Pitt and colleagues at Mount Sinai School of Medicine who have a history of research in areas related to the identification and characterization of cellular processes within the kidney. It also seeks to develop new directions of investigation using electrophysiological, cell biological, molecular and genetic tools and to attract new investigators to kidney research.

• Kyong Bae of medicine was awarded $770,000 from NIH for “Identifying CT Imaging Biomarkers Associated With Prognosis of Pulmonary Embolism.” The project aims to advance the understanding of the risk and recurrence of pulmonary embolisms and provide a new insight into the prognosis for patients with pulmonary embolisms and the clinical management and treatment of the condition.

• Kim Sutton Tyrrell of the Graduate School of Public Health’s epidemiology department was awarded a continuation grant of nearly $700,000 from NIH for a clinical trial aimed at reversing arterial stiffening.

The researchers seek to test whether the vascular effects of obesity in young adults are reversible with weight loss, increases in activity and reduced sodium intake.

• Thomas Hales of mathematics was awarded $446,000 in a three-year NSF grant for the formal proof of the Kepler conjecture.

One of the oldest problems in geometry, the Kepler conjecture asserts that a pyramid is the most efficient way to stack spheres.

Hales’s proposal provides details about how the published text of the proof of the Kepler conjecture is to be converted to data structures or computer programs. Another part of the research gives details about how to automate the proofs of a collection of problems in geometry.

This proposal has the potential to reshape the way mathematicians approach large-scale computer-assisted proofs.


Bypassing the blues

Coronary artery bypass graft (CABG) patients who were screened for depression after surgery and then cared for collaboratively by a nurse-led team of health care specialists reported better quality of life and improved physical function than those who received their doctors’ usual care, according to a study from the School of Medicine. The approach has proven effective for treating major depression in primary care settings but had never before been applied to a population with cardiac disease.

The main outcomes of the study were presented recently at the annual meeting of the American Psychosomatic Society.

CABG surgery is one of the most frequently performed and costly medical procedures in the United States. Depressive symptoms are common following CABG surgery and are associated with worse clinical outcomes, including poorer quality of life, continued chest pains and higher risk of re-hospitalization and death.

Bruce L. Rollman of the Center for Research on Health Care and professor of medicine and psychiatry, said: “Few depression treatment trials have been conducted in patients with cardiac disease, and none used the collaborative care model or examined the impact of treating post-CABG depression on quality of life, re-hospitalizations or health care costs, as we did.”

Investigators recruited 453 post-CABG patients at seven Pittsburgh-area hospitals, 2004-07. They included 302 depressed patients who randomly were assigned either to an eight-month course of telephone-delivered collaborative care or to their doctors’ usual care for depression. Investigators also randomly sampled an additional 151 non-depressed, post-CABG patients to facilitate comparisons to depressed patients. They tracked these patients for up to four years to monitor quality of life, physical functioning, mood symptoms, re-hospitalizations, health care costs and deaths. Analysis of the data is ongoing.

Pitt co-authors were Wishwa N. Kapoor, professor of medicine, Division of General Internal Medicine, and director of the Center for Research on Health Care; Charles F. Reynolds III, Department of Psychiatry, Western Psychiatric Institute and Clinic; Sati Mazumdar, biostatistics, Graduate School of Public Health; Patty Houck, statistical services administrator in GSPH; Peter Counihan, Cardiovascular Institute; Bea Herbeck Belnap, senior research associate in the Department of Medicine, and Pitt psychiatry professor emeritus Herbert C. Schulberg of Weill Cornell Medical School.


Optimists live longer

In a large study of post-menopausal women, optimists had decreased rates of death and were less likely to be hypertensive, diabetic and smokers than pessimists, according to researchers at the School of Medicine. In addition, women identified as highly mistrustful of other people had increased rates of death when compared to their less “cynically hostile” counterparts. The results of the research were presented recently at the American Psychosomatic Society’s annual meeting.

The study, led by Hilary Tindle, professor of medicine in the Division of Internal Medicine, analyzed data from nearly 100,000 women in the Women’s Health Initiative, an NIH-funded study that has followed women ages 50 and over since 1994, with follow-up ongoing.

Optimism was defined as the expectation that good, rather than bad, things will happen. Optimists in the group had a decreased rate of death and were 30 percent less likely to die from coronary heart disease than pessimists. Those identified as being more cynically hostile had a higher rate of death and were 23 percent more likely to die from a cancer-related condition.

For the study, optimism and cynical hostility were not compared directly. Rather, optimists were compared to pessimists, while women with a high degree of cynical hostility were compared to those with a low degree of cynical hostility.

Interestingly, results for optimism and cynical hostility appeared more pronounced in the almost 8,000 black women surveyed. Optimistic black women had a lower rate of death and a 44 percent reduction in risk of cancer-related death. Alternatively, the most cynically hostile black women had a higher rate of death and a 142 percent increase in risk of cancer-related death. Tindle notes these results need to be interpreted with caution because of the low number of black women surveyed.

Pitt co-authors of the study included Yue-Fang Chang of neurological surgery, Lewis H. Kuller of epidemiology and Greg J. Siegle and Karen Matthews of psychiatry.


Kids with bipolar parents at greater risk

A School of Medicine study published in the March issue of Archives of General Psychiatry finds that children and teens of parents with bipolar disorder have an increased risk of early-onset bipolar disorder, mood disorders and anxiety disorders.

Researchers suggest that having family members with bipolar disorder is the best predictor of whether children will go on to develop the condition.

Boris Birmaher, director of the Child and Adolescent Anxiety Program and co-director of Child and Adolescent Bipolar Services at WPIC, said, “A bipolar diagnosis at a young age deprives children of the opportunity to experience normal emotional, cognitive and social development, and this is why there is an urgent need to identify, diagnose and treat these patients early on.”

Compared with the offspring of control parents, children with bipolar parents had a 14-fold increased risk of having a bipolar spectrum disorder, as well as a two- to three-fold increase of having a mood or anxiety disorder.

Children in families where both parents had bipolar disorder also were more likely to develop the condition than those in families containing one parent with bipolar disorder. However, their risk for other psychiatric disorders was the same as children who had one bipolar parent.

Study co-authors were David Axelson, Kelly Monk, Catherine Kalas, Benjamin Goldstein, Mary Beth Hickey, Mihaela Obreja, Mary Ehmann, Satish Iyengar, Warl Shamseddeen, David Kupfer and David Brent, all from the Department of Psychiatry and WPIC.

This study was supported in part by the National Institute of Mental Health.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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