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Chasing schizophrenia
A newly identified genetic pathway could lead to drugs that slow mental illness
Over the past decade, Maria Karayiorgou and her colleagues have narrowed the search for the genetic roots of schizophrenia. Today, Karayiorgou’s lab is primarily focused on two small areas on chromosomes 8 and 22 that likely harbor genes that influence susceptibility to the mental illness.
Last year, working with scientists in the United States and South Africa, Karayiorgou completed a systematic scan on one of those regions and identified several individual genes as strong candidates.
Now a recent study of over 400 families with a history of schizophrenia confirms she’s on the right track.
After conducting genetic studies on the families, Karayiorgou discovered that one set of genes, known as PPP3CC and believed to code for a subunit of calcineurin, was present in 38 percent of the parents’ chromosomes – and was transmitted to children with schizophrenia more times than would be expected by chance.
In another study, conducted by Karayiorgou’s colleagues at MIT and Columbia University, scientists looked at mice that were genetically altered to lack an enzyme called calcineurin, which has roles in the immune system and the brain. The result: the mice had behavioral abnormalities, including memory impairment and social withdrawal, that were similar to those seen in people with schizophrenia.
“Based on our examination of 410 families with a history of schizophrenia and a new mouse model of schizophrenia, we have obtained several lines of converging evidence that show a disruption in calcineurin signaling plays a role in the development of schizophrenia,” says Karayiorgou, head of the Laboratory of Human Neurogenetics.
The findings illustrate why schizophrenia researchers look not only at individual genes, but also at groups of genes. “We are now thinking more in terms of pathways rather than one gene at a time. Different genes in a given pathway may be malfunctioning in different patients with the same end result,” she explains. Based on this hypothesis, Karayiorgou has extended her search to look at other genes in the calcineurin pathway – and other pathways – using genetic screening techniques.
Eventually, the research could lead to drugs that selectively target and block the function of specific genetic pathways that contribute to the development and progression of schizophrenia. That would mean a better life for millions of sufferers who have trouble with memory as well as deficits in emotional and social behavior. About one percent of the population worldwide is affected by the disease.

September 25, 2003



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