Two new studies provide the strongest evidence yet that schizophrenia is a genetic disease and shed further light on how it progresses on a molecular level. The findings may lead to the design of better antipsychotic drugs, say the researchers.
Many scientists have assumed that schizophrenia is caused by environmental influences, such as viral infections or psychological stress. But a genetic case for the disease was bolstered in 2000 when J. Kirsty Millar of the University of Edinburgh, United Kingdom, found that a number of Scottish schizophrenics shared a mutation in a gene called DISC1. Not all researchers were convinced of the gene's significance, however, because Millar's study was limited to a single family.
Now two studies provide further evidence of DISC1's role in the development of schizophrenia. As reported online yesterday in Nature Cell Biology, Akira Sawa of Johns Hopkins University in Baltimore, Maryland, and colleagues disrupted DISC1 expression in the brains of mouse embryos using a technique called RNA interference. Compared to controls, the mice experienced a severe delay in the migration of neurons in their brains, leading to abnormal brain development. What's more, the neurons themselves were improperly oriented in a pattern that matched that seen in the brains of human schizophrenics. This is the first time DISC1 dysfunction has been linked to schizophreniclike abnormalities in living brain tissue, says Sawa.
Sawa's paper comes just days after another DISC1 study by Millar's group. The team, whose results were published in the 18 November Science, used fluorescent dyes to map the DNA of two related human schizophrenics and found they both had a mutation in PDE4B--a gene known to affect learning, memory, and mood. Normally, the DISC1 protein binds to a specific region of the PDE4B protein, but this interaction did not take place in the schizophrenic subjects. The team proposes this probably occurred because of a mutation in the DISC1 protein. Though the complete molecular mechanism must be worked out first, both Sawa and Millar point to DISC1 as a logical target for the future design of antipsychotic drugs.
"These are two exciting papers," says Carol Tamminga, a clinical researcher at the University of Texas Southwestern Medical Center in Dallas. She cautions against focusing solely on DISC1 however, noting that other genes are likely to play roles in schizophrenia. Even if researchers do focus on DISC1, developing drugs "will be very challenging," says L. Fredrik Jarskog, a molecular biologist who studies antipsychotic medications at the University of North Carolina at Chapel Hill. That's because DISC1 has its biggest impact in early fetal development. "You can't really undo what it did," he says, "because by adulthood things have become hardwired."