Researchers at Washington University School of Medicine in St. Louis have received a five-year, $2.7 million grant to detect and analyze differences in the brains of children with a rare illness, Wolfram syndrome.

The disorder, which is caused by mutations in a single gene, includes a severe form of diabetes, hearing and vision loss and kidney problems. Eventually, patients lose muscle control and coordination due to degeneration in the brain. More than half of the patients die before they turn 40, often due to atrophy in the brainstem that contributes to respiratory failure. The illness affects an estimated one in 770,000 children.

As part of the new study, researchers will conduct MRI scans to measure and quantify changes in the brain during the course of the disorder.

“In preliminary studies, we have been able to detect differences in the size and volume of several brain structures in kids who have Wolfram syndrome,” says principal investigator Tamara Hershey, PhD, professor of psychiatry, of neurology and of radiology. “Our goal in the new study is to look for patterns of changes in the brain that might help us identify problems earlier, with the eventual hope of being able to intervene.”

Hershey says work in animal models of Wolfram syndrome is progressing rapidly toward possible interventions and treatments, so it is important to better understand how the disorder develops and progresses. She says using MRI scans and conducting behavioral testing to measure changes in the brain provide an opportunity to do that.

“The neurological features of the disease may be the most feasible thing to target and monitor in clinical trials,” she explains. “That’s because by the time a child gets a diagnosis of Wolfram syndrome, the insulin-producing cells in the pancreas already are damaged or destroyed, and the child has developed insulin-dependent diabetes. By identifying time points at which it’s possible to intervene, we may be able to prevent some of the severe problems that occur later in the course of Wolfram syndrome.”

Hershey

Hershey’s group already has identified some key differences in the brainstem and the cerebellum. They have learned that in children with Wolfram syndrome, those structures tend to be smaller than those of other children their age, and there are differences in the thickness of the brain’s cortex, especially in an area related to vision.

By tracking patients with Wolfram syndrome over time with regular MRI scans and other neurological tools, Hershey says it may be possible to distinguish between changes that occur as the brain develops during childhood and those that occur due to degeneration related to the disorder.

Wolfram syndrome is caused by mutations in the WSF-1 gene, which was first identified in 1998 by the late M. Alan Permutt, MD, a former professor of medicine and of cell biology and physiology at the School of Medicine. He later developed an animal model of the disorder and set up an international patient registry.

In 2010, Washington University organized the world’s first, multidisciplinary clinic for patients with Wolfram syndrome, funded in part by the Snow Foundation, a family organization dedicated to raising funds for Wolfram syndrome research. Children worldwide came to St. Louis for testing and evaluation. Those clinics now are an annual event at St. Louis Children’s Hospital.

The Internet address for the Wolfram Syndrome International Registry’s website is  http://wolframsyndrome.dom.wustl.edu/medical-research/Wolfram-Syndrome-Home.aspxWashington University School of Medicine’s 2,100 employed 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 sixth 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.

August 7, 2012

The bright green spots are TXNIP molecules, potential treatment targets for diabetes and Wolfram syndrome.

Now a molecule has been identified that’s key to the cell stress-modulated inflammation that causes insulin cells to die, report scientists at Washington University School of Medicine in St. Louis, the University of Massachusetts Medical School in Worcester and elsewhere.

“There are two types of inflammation,” says senior investigator Fumihiko Urano, MD, PhD. “There is local inflammation within cells that can be caused by a specific type of cell stress named ER stress. There’s also systemic inflammation that involves the activation of immune system cells. The molecule we’ve identified is involved in the initiation of local inflammation that can lead to systemic inflammation.”

That molecule, called thioredoxin-interacting protein (TXNIP), provides scientists with a target to direct therapies for diabetes and Wolfram syndrome. The latter disorder causes kidney problems as well as hearing and vision loss. As patients get older, they develop ataxia, a brain dysfunction that causes a loss of muscle control and coordination, and many patients die before their 40th birthday.

The new study is published Aug. 8 in the journal Cell Metabolism.

Urano, an associate professor of medicine in Washington University’s Division of Endocrinology, Metabolism and Lipid Research, studies a type of cell stress known as endoplasmic reticulum (ER) stress. The endoplasmic reticulum is part of a cell that’s responsible for producing proteins and synthesizing cholesterol. Every cell in the body has an endoplasmic reticulum, which also is involved in transporting proteins to the parts of the cell where they are needed.

In ER stress, misfolded proteins accumulate, activating a response in the cell designed to correct the problem by making fewer proteins and eliminating the misfolded ones. But if the stress cannot be resolved, the cells self destruct.

“The endoplasmic reticulum does many important things,” Urano says. “When it doesn’t function properly, it can contribute to several different diseases. In the case of Wolfram syndrome and diabetes, we believe that dysfunction within insulin-secreting cells causes ER stress, which, in turn, contributes to local inflammation and cell death.”

Urano’s team analyzed genes that were activated in insulin-producing cells under ER stress and found that TXNIP was manufactured in large amounts in the stressed cells. Past research demonstrated that the protein was involved in inflammation, and as experiments progressed, the researchers were able to link TXNIP both to ER stress within the cell and to inflammation outside of specific populations of cells that can have an effect throughout the body.

Dr. Fumikho Urano

“We found that ER stress can lead to inflammation activation through the TXNIP protein,” he says. “So if we could somehow block TXNIP, we may be able to mitigate the inflammation and block the progression of diabetes and Wolfram syndrome.”

Urano has found that in animal models of Wolfram syndrome, TXNIP levels are significantly increased in insulin-secreting cells. Meanwhile, other recent research has discovered that a common blood pressure medication called verapamil can interfere with TXNIP production, so Urano’s team plans to test that drug in animals with Wolfram syndrome to learn whether it might delay the progression of the disease. Those experiments, Urano says, are under way.

The TXNIP protein provides the best available target for therapies because the only other known molecule involved in cell death under ER stress conditions is housed in the cell nucleus, he says. TXNIP, on the other hand, exists outside the nucleus and therefore may more easily interact with potential therapeutic agents.

Although this study involves the extremely rare disorder Wolfram syndrome, which affects about one in 500,000 people, Urano says the findings may be important to many other diseases because inflammation contributes to so many disorders, from heart disease to cancer.

“Local inflammation such as ER stress can’t be detected by looking for inflammatory molecules in blood plasma, but it is very important in the pathogenesis of many chronic human diseases,” he says. “By studying TXNIP in Wolfram syndrome, we may be able to uncover clues for treating other chronic diseases, including neurodegenerative diseases, such as Alzheimer’s disease and similar illnesses that cause cognitive problems.”

Oslowski CM, Hara T, O’Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner DL, Kaufman RJ, Bortell R, Urano F. Thioredoxin-interacting protein mediates ER stress-induced beta cell death through the initiation of the inflammasome. Cell Metabolism, vol. 16 (2), Aug. 8, 2012.

Funding for this research comes from the JDRF and from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). NIH grant numbers DK067493, DK016746, DK042394, DK088227, DK93074, DK080339, P60 DK020579, RR024992, UL1 TR000448, HL057346 and HL052172.

Washington University School of Medicine’s 2,100 employed 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 sixth 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.