New schizophrenia pathway discovered by chance

Researchers at the Hopkins School of Medicine have unexpectedly shown that three separately identified proteins actually interact in a pathway that, when disrupted, plays a role in schizophrenia.

This collaborative study spanned three Hopkins labs. The newly uncovered pathway presents new targets for drugs to treat the illness, and also suggests a new way to study other mental illnesses.

The scientists found that the proteins BBS4, DISC1 and PCM1 work together to influence how neurons, or nerve cells, develop in the brain's cerebral cortex. Abnormal development in the cerebral cortex is widely believed to be the underlying cause of schizophrenia, a devastating psychiatric illness.

The idea for the collaboration was sparked in 2004 when Nicola Cascella, a Hopkins psychiatrist, read a paper published by Nicholas Katsanis, a Hopkins geneticist. Katsanis had been studying Bardet-Biedl syndrome, a genetic disease characterized by obesity, extra fingers or toes, retarded growth and other health problems.

One of the proteins Katsanis researched, BBS4, was found in the lab to bind to another protein called PCM1, near the centrosome in neurons. The centrosome is a structure that is involved in the growth and division of cells.

With what he described as "real serendipity," Cascella realized that Katsanis's research could be related to schizophrenia. "What struck me was that ... Bardet-Biedl syndrome causes problems with body symmetry," Cascella said. "Schizophrenic brains indeed have problems with symmetry - actually the loss of the normal asymmetry between left and right brain regions."

Cascella brought Katsanis together with Hopkins researcher Akira Sawa. Along with Atsushi Kamiya, Sawa was studying the DISC1 protein's role in neuronal cell growth and how abnormalities in it affected schizophrenia. Cascella hypothesized that the three proteins, DISC1, BBS4 and PCM1, would all bind to each other in the cell.

Working together, they tagged the proteins and discovered that all three did in fact end up at the cell centrosome. Additionally, when either DISC1 or BBS4 were knocked out, PCM1 was not able to reach the centrosome. They concluded that the proteins DISC1 and BBS4 were acting together to help PCM1 reach the centrosome and in turn allow normal neural cell development.

According to Sawa, this coordinated interaction between the three proteins is especially important "in the context of neurodevelopment of the cerebral cortex in the brain, which is a site of a key pathogenesis of schizophrenia and related disorders."

Finally, the scientists studied a family with three cases of schizophrenia and found that those with the disease had a mutation in the PCM1 gene while those without the disease did not. "The mutated gene is linked to a clear molecular pathway that has an action on neurodevelopment," Sawa said.

The project was an "opportunity for wonderful collaboration," Katsanis said. "It was scientifically fun and good personal collaboration. We got [along] together very well."

Next, the scientists plan to look closely at DISC1 and other proteins in the BBS family. These proteins not only affect the centrosome, but are active in other parts of the neuron that may be important in schizophrenia. They have also received funding from the National Institutes of Health to study mutations of these genes in animal models for schizophrenia.

This model of study can be applied to other psychiatric illnesses and also provides new targets for drugs to treat schizophrenia.

When asked if he was surprised that the project came together across three different labs, Katsanis said, "I'm not surprised by anything in science anymore. It is the unexpected interfaces that produce the most exciting science. The door has opened up to a whole new world."