The study, reported this week in the early online edition of the Proceedings of the National Academy of Sciences, may lead to the first genetically targeted drugs for the disease, which affects 1 percent of the population worldwide.
Nobel laureate Susumu Tonegawa, director of the Picower Center for Learning and Memory at MIT and a Howard Hughes Medical Institute investigator, found that genetically engineered mice lacking the brain protein calcineurin exhibit a number of behavioral abnormalities shared by schizophrenic patients.
In a related study with researchers at Rockefeller University in New York, MIT scientists show that variation in a human calcineurin gene also is associated with schizophrenia. Calcineurin--part of a biochemical pathway in the brain linked to receptors for two brain chemicals, NMDA and dopamine--plays a significant role in the central nervous system.
This is the first study that uses animals who demonstrate an array of symptoms observed in schizophrenic patients to identify specific genes that predispose people to the disease.
MICE AND MEMORY
Tonegawa creates tools to explore the genetic underpinnings of the molecular mechanism for memory. Genetically engineered mice who are missing the brain enzyme calcineurin were previously shown to have an impairment in short-term, day-to-day memory formation, known as working memory. This kind of memory also is impaired in schizophrenia patients.
Further testing of these mice by Picower Center research scientist Tsuyoshi Miyakawa revealed that they also have attention deficits, aberrant social behavior and several other abnormalities characteristic of schizophrenia.
Picower Center research scientist David Gerber then collaborated with Rockefeller’s Maria Karayiorgou to examine calcineurin genes in DNA samples from schizophrenic patients and their immediate relatives. The researchers found an association between a particular calcineurin gene and schizophrenia.
"This is an intriguing series of findings," Tonegawa said. "The combination of evidence from the genetically altered mice, together with the human gene studies, create a strong argument to link calcineurin with schizophrenia."
A SEARCH FOR DRUGS
Alterations in multiple genes are believed to predispose people to schizophrenia. Tonegawa suspects that many of these genes may turn out to be components of the calcineurin pathway or to directly interact with the calcineurin pathway.
"Once we better understand exactly which genes are involved, we will know how proteins are affected, and we can set up a test to screen large numbers of compounds to identify ones that have desired effects on the activity of these proteins," Tonegawa said. "This can potentially lead to the discovery of new kinds of drugs for psychiatric conditions such as schizophrenia."
In addition to Gerber, Miyakawa, Karayiorgou and Tonegawa, co-authors include Joseph A. Gogos of Columbia University, and Diana Hall and Sandra Demars of Rockefeller University. Authors on the mouse study include research specialist Lorene M. Leiter and Hongkui Zeng of MIT, and Raul R. Gainetdinov, Tatyana D. Sotnikova and Marc G. Caron of Duke University.
The study on the human genes associated with schizophrenia susceptibility was funded by the Picower Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Otsuka Maryland Research Institute, the McKnight Endowment Fund for Neuroscience, the EJLB Foundation and the New York City Council Speaker’s Fund.
The study on the genetically altered schizophrenic mice was funded by the Picower Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, RIKEN and NARSAD.
MIT News Office
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