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 Research & Giving News Article  "This is very exciting because until now the many known genetic factors implicated in schizophrenia were not connected in any way," said Akira Sawa, M.D., Ph.D., a 2002 and 2004 NARSAD Young Investigator and recipient of NARSAD’s 2007 Staglin Award for Schizophrenia Research, whose team recently reported the findings in The Archives of General Psychiatry. Dr. Sawa is director of the program in molecular psychiatry and associate professor of psychiatry and neuroscience at Johns Hopkins University School of Medicine. “Now, we not only have figured out how these three proteins interact with each other,” Dr. Sawa said, “we also have found patients who carry mutations. These results give us a really good foundation to dig deeper into schizophrenia, which has proven to be such an elusive illness.” A tale of three proteins Dr. Sawa's team previously had characterized a leading “candidate” gene for schizophrenia, the so-called DISC1 (“Disrupted in Schizophrenia-1”) gene. The protein that this gene directs cells to manufacture is required for proper nervous system development. Disruption of the gene has been linked to schizophrenia in a subset of patients. Dr. Sawa’s team also had previously shown that the DISC1 protein binds to a protein called PCM1 in a structure within the nucleus of cells called the centrosome, which plays a key role in the coordination of cell division and cell structure. Separately, Johns Hopkins geneticist and associate professor of ophthalmology Nicholas Katsanis, Ph.D., and his team were studying an unrelated family of proteins and had discovered that one of them, BBS4, also is found near the centrosome and also binds to PCM1. It was Johns Hopkins psychiatrist Nicola Cascella, M.D., a 2000 NARSAD Young Investigator and currently co-director of the program in molecular psychiatry and assistant professor of psychiatry at Hopkins, who, according to Dr. Sawa, “brought it all together” by realizing that the behavioral defects seen in patients with a rare condition called Bardet-Biedl Syndrome and the molecular interaction of BBS4 and PCM1 could be related and relevant to schizophrenia. To show that the three proteins do in fact physically interact with each other in a cell, the research teams attached different chemical “tags” to each protein and followed them 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 team’s 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,” Dr. Cascella said. “This is a molecular pathway that we can potentially target for drug therapy.” This article was adapted by NARSAD with permission of Johns Hopkins University School of Medicine. |
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