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Hopkins researchers piece together gene 'network' linked to schizophrenia
Date:9/2/2008

tients and the molecular interaction of BBS4 and PCM1 could be related and relevant to schizophrenia.

"Serendipity brought us together from the far corners of campus and allowed us to see the links between these three proteins, centrosomes, and schizophrenia," says Katsanis. So they embarked on a collaboration to see if these coincidental observations would lead to a better understanding of schizophrenia.

First, to show that the three proteins do in fact physically interact with each other in a cell, the research teams attached different tags to each protein and followed the proteins in cells grown in the lab. They found that all three proteins do end up together, at the centrosome. When the researchers removed either DISC1 or BBS4 from cells, PCM1 would not make it to the centrosome, leading the researchers to conclude that DISC1 and BBS4 act together to recruit PCM1.

The researchers then asked if the failure of PCM1 recruitment to the centrosome in mice lacking either DISC1 or BBS4 affects brain development. To do this they reduced the amount of each of the three factors in the brains of developing mice. As a result, nerve cells in the cerebral cortex-the part of the brain responsible for memory and thought-failed to grow properly, suggesting that these three proteins act together synergistically during normal brain development.

The teams' next question was whether PCM1 could contribute to schizophrenia. By examining DNA from families with schizophrenia, the researchers discovered a mutation in PCM1 in one family, but only carried by family members who had been diagnosed with schizophrenia.

"This connection is exactly the sort of daisy chain from gene to disease that psychiatrists pray for," says Cascella. "This is a molecular pathway that we can potentially target for drug therapy."

"We are beginning to sub-stratify psychiatric illness into discrete molecular causes," adds Katsanis. "Now that we know
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Contact: Audrey Huang
audrey@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
Source:Eurekalert

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