According to a study published February 6 in the online edition of the journal Proceedings of the National Academy of Science USA (PNAS), a "master" regulatory molecule in the brain that is mutated in individuals with schizophrenia, has been identified by a team of researchers led by Claes Wahlestedt, M.D., Ph.D., of the University of Miami Miller School of Medicine's associate dean for therapeutic innovation.
This finding could help researchers develop more effective drugs for Schizophrenia, a debilitating psychiatric disorder that affects approximately 1% of all individuals worldwide. The study is entitled "MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function."
The team identified miR-132, a "master" gene regulatory microRNA molecule, and discovered altered levels of miR-132 localized in the frontal region of the brain cortex in individuals with schizophrenia.
This area of the brain is responsible for higher order cognitive function and has been linked to schizophrenia symptoms, including:
- Social withdrawal
- and impaired cognitive function
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, explains:
"Schizophrenia has been difficult to treat precisely because many different genes and brain systems are affected. 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 problem, without causing side effects associated with current treatments that can be so severe that many patients stop using them."
Due to the complexity of schizophrenia, with abnormalities recorded in multiple brain signaling pathways, as well as in the complexity and size of functional brain regions and individual nerve cells, earlier investigations into the disease have been restricted.
In addition, years of research have identified several genes associated to schizophrenia, although each gene is likely to only contribute a little to the pathology of the disorder, and may only be relevant in a sub-population of patients.
According to Wahlestedt, overarching epigenetic mechanisms could be the missing link between environmental factors that contribute to diseases, such as schizophrenia, and the interaction of one's genetic predispositions.
Together with his team, Wahlestedt speculate that several of the biological changes seen in schizophrenia could be explained by the alterations in just a few "master" regulatory molecules. The team focused on microRNAs, a recently-identified class of regulatory small RNAs, which of are of increasing interest to scientists investigating several different human illnesses, including schizophrenia.
Humans have approximately 1,000 microRNAs, which are expressed more in the brain than in any other tissue. Just one microRNA can control the expression of several hundred genes. MicroRNAs are at the center of biological networks that are vital for brain development, function of neurons, and proper wiring of neuronal circuits.
The team assessed the expression of 850 microRNAs in dorsolateral prefrontal cortical tissue in 100 individuals with schizophrenia, bi-polar and control subjects. They discovered that miR-132 was the only microRNA considerably disrupted in individuals with schizophrenia compared to the control group.
Furthermore, the researchers discovered that miR-132 is linked to numerous neurodevelopmental changes during adolescence and early adulthood (the most prevalent age of onset for schizophrenia), and that it controls over 10% of genes known to be abnormally expressed in the brains of adult individuals with 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."
The team are hopeful that their finding of miR-132 will result in the development of more effective medications for schizophrenia, which costs the United States over $100 billion per year. Schizophrenia takes a terrible toll on patients, who have increased risk for other diseases and high suicide rates, and on their family 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 Researh, Ocean Ridge Biosciences, and RexGen Inc.
Written by Grace Rattue