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2.06.2012

Miller School Study Identifies Master Regulator for Schizophrenia

A team of researchers led by Claes Wahlestedt, M.D., Ph.D., the Miller School’s associate dean for therapeutic innovation, has pinpointed a “master” regulatory molecule in the brain that is altered in people with schizophrenia. The finding could facilitate the development of better drugs for the debilitating psychiatric disorder that affects an estimated one percent of the world’s population.

Published February 6 in the online edition of the prestigious scientific journal Proceedings of the National Academy of Science USA (PNAS), the study, “MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function,” identified a “master” gene regulatory microRNA molecule, miR-132, and found altered levels of miR-132 localized in the frontal region of the brain cortex in schizophrenic subjects. The region is responsible for higher order cognitive function and has been strongly associated with symptoms of schizophrenia, including hallucinations, paranoia, psychosis, social withdrawal, and impaired cognitive function.

The study, which will be highlighted in the “In This Issue” feature of the February 21 print edition of PNAS, suggests that miR-132 regulates a large set of genes that are important during embryonic neurodevelopment, adolescent brain development and adult brain function. Therefore, altered miR-132 levels could underlie neuronal abnormalities associated with schizophrenia.

“Schizophrenia has been difficult to treat precisely because many different genes and brain systems are affected,” says Wahlestedt, who is also vice chair for research in the Department of Psychiatry and Behavioral Sciences and director of The Center for Therapeutic Innovation at the John P. Hussman Institute for Human Genomics. “The identification of a key regulatory molecule like miR-132 will allow us to better understand what goes wrong biologically in schizophrenia, and design medications that address the specific problems, without causing side effects associated with current treatments that can be so severe that many patients stop using them.”

Previous studies examining schizophrenia have been hampered by the complexity of the disease, with abnormalities documented in a myriad of brain signaling pathways, and in the size and complexity of both individual nerve cells and functional brain regions. Furthermore, decades of genetic studies have identified numerous schizophrenia-associated genes, but each likely contribute in a very minor way to the pathology of schizophrenia, and may be relevant only in a sub-population of patients.

Wahlestedt’s lab focuses on overarching epigenetic mechanisms, and he believes they could be the missing link between the interaction of one’s genetic predispositions and environmental factors that contribute to diseases such as schizophrenia. He and his collaborators hypothesized that alterations in just a few key “master” regulatory molecules could explain many of the biological changes observed in schizophrenia. In the PNAS study, they focused on microRNAs, a recently-discovered class of regulatory small RNAs, which are of growing interest to researchers studying many different human illnesses, including schizophrenia.

Humans, Wahlestedt explains, have on the order of 1,000 microRNAs, which are expressed more in the brain than in any other tissue. A single microRNA can regulate the expression of several hundred genes, placing microRNAs at the center of biological networks that are crucial for the development of the brain, proper wiring of neuronal circuits and function of neurons.

In the PNAS study, Wahlestedt and his team evaluated the expression of 850 microRNAs in dorsolateral prefrontal cortical tissue from 100 control, schizophrenic and bi-polar subjects, and found that only one, miR-132, was significantly disrupted in schizophrenic patients compared to the control patients. They also found that miR-132 regulates more than 10 percent of genes known to be abnormally expressed in the brains of adult schizophrenic patients. Last, they found that miR-132 is associated with a number of neurodevelopmental changes during adolescence and early adulthood, the most common age of onset for schizophrenia.

“These changes are critical for regulating the correct wiring and activity of the frontal cortex, and disruption during early life may result in schizophrenia,” Wahlestedt said.

Since efforts to develop better drugs have been stymied by the limited understanding of the biological mechanisms that cause schizophrenia, Wahlestedt and his collaborators are hopeful their miR-132 finding will lead to improved medications for the chronic, severe and disabling brain disorder, which costs the U.S. more than $100 billion a year. In addition to the high monetary costs, schizophrenia exacts a terrible toll on patients, who have high rates of suicide and elevated risk for other diseases, as well as on their families and friends.

In addition to Wahlestedt, senior author of the study, co-authors include first author Brooke H. Miller, Ph.D., research associate at the Scripps Research Institute-Florida, and from the Miller School, Zane Zeier, Ph.D., assistant scientist in the Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation at the Hussman Institute. Other collaborators include researchers from Scripps, the German Center for Neurodegenerative Diseases, Yale University School of Medicine, Pfizer Global Research, Ocean Ridge Biosciences, and RexGen Inc.

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