Schizophrenia Genes may Provide Potential Drug Target

by Rajashri on Sep 4 2008 3:40 PM

Scientists at the Johns Hopkins University School of Medicine have put together a 'gene' network associated with schizophrenia, which could pave the way for new drugs in future.

The network consists of three previously known, yet unrelated proteins- DISC1 gene and protein, PCM1 protein and BBS4.

"This is very exciting because until now the many known genetic factors implicated in this condition were not connected in any way," said Akira Sawa, M.D., Ph.D., director of the program in molecular psychiatry and associate professor of psychiatry and neuroscience at Hopkins.

He added: "Now, through a cross-disciplinary and cross-departmental collaboration, we not only have figured out how these three proteins interact with each other, we also have found patients who carry mutations. These results give us a really good foundation to dig deeper into such an elusive condition."

His team had earlier found that DISC1 gene and protein, which are required for proper nervous system development, significantly contribute to schizophrenia when disrupted. They also had shown that DISC1 protein binds to PCM1 protein at the centrosome, which coordinates the structure and movement of cells.

In another study, a team led by Hopkins geneticist and associate professor of ophthalmology Nicholas Katsanis, Ph.D., found that BBS4, belonging to an unrelated family of proteins, is also found near the centrosome and also binds to PCM1.

"But we weren't thinking schizophrenia at the time because BBS4 is involved in Bardet-Biedl Syndrome, which is a wide-ranging condition mainly known for its associated eye and and kidney problems but also does cause behavioral defects in some patients," said Katsanis.

But it was Hopkins psychiatrist Nicola Cascella, M.D., co-director of the program in molecular psychiatry and assistant professor of psychiatry who, according to Sawa, "brought it all together" by realizing that the behavioural defects seen in Bardet-Biedl Syndrome patients 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," said Katsanis.

Firstly, the researchers 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.

Later, they reduced the amount of each of the three factors in the brains of developing mice. Thus, 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.

Later the team wanted to find out if PCM1 could contribute to schizophrenia. And for this, they examined DNA from families with schizophrenia and 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. This is a molecular pathway that we can potentially target for drug therapy," said Cascella.

The study was reported this week in the Archives of General Psychiatry.