EVENTS | VIEW CALENDAR
Getting the signals crossed
LONDON—Schizophrenia may be caused by faulty signaling in the brain, according to genetic research published recently in the journal Molecular Psychiatry by researchers at Imperial College London and GlaxoSmithKline (GSK)—conducting what is said to be the biggest study of its kind to examine in detail brain samples donated by people with the condition.
Using microarray technology, the team set out to determine the expression of more than 30,000 messenger RNA (mRNA) transcripts in post-mortem tissue from a brain region associated with the pathophysiology of schizophrenia (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. Then they compared their samples, called the Charing Cross Hospital prospective collection, with that of an independent prefrontal cortex dataset from the Harvard Brain Bank in the United States.
The researchers found 51 gene expression changes that were common between the schizophrenia cohorts and of those, they identified 49 genes that work differently in the brains of schizophrenia patients compared to control patients.
According to Jackie de Belleroche, a professor in the Division of Neurosciences and Mental Health at Imperial College London and the corresponding author of the paper, many of these genes are involved in controlling cell-to-cell signaling in the brain, supporting the theory that abnormalities in the way cells "talk" to each other are involved in the disease.
"The first step towards better treatments for schizophrenia is to really understand what is going on, to find out what genes are involved and what they are doing," notes de Belleroche. "Our new study has narrowed the search for potential targets for treatment."
In addition to identifying signaling as a possible cause of schizophrenia, the new findings could also lead to new ways of diagnosing the condition instead of the current ones, under which patients are diagnosed on the basis of their behavior alone.
"Most patients are diagnosed as teenagers or in their early 20s, but if they could be diagnosed earlier, they could be treated more effectively and they could have a better quality of life," de Belleroche says. "To have the possibility of transforming someone's life early on instead of having to take drugs indefinitely would be wonderful."
This work, part of a collaboration between Imperial College and GSK's Harlow, U.K.-based R&D facility, is part of a larger study looking at proteins, DNA and mRNA in the samples, which were taken from two brain regions associated with schizophrenia: the frontal cortical area and the temporal cortex.
Although schizophrenia isn't one of the key areas of focus at GlaxoSmithKline, the company does have a Phase II compound, known as 773812, in the pipeline for the condition—part of a much larger "innovative neuroscience pipeline" the company began touting in late 2007—and GSK invested roughly $13 million a little over a year ago in Singapore's biotechnology hub, Biopolis. That investment was part of GSK's Center for Research in Cognitive and Neurodegenerative Disorders, which was created to focus on discovering drugs to help cure Alzheimer's disease and schizophrenia.
Schizophrenia is believed to affect roughly 1 percent of the population. Symptoms vary but can include hallucinations, lack of motivation and impaired social functioning. The disorder has little physical effect on the brain, though, and so its causes have remained largely unknown.
Some scientists believe that schizophrenia could be caused by the brain producing too much dopamine, partly because drugs that block dopamine action provide an effective treatment for the condition. In fact, Marc Laruelle, an Imperial College professor and chair of biological psychiatry at Charing Cross Hospital—one of Imperial College's teaching hospitals—gave a presentation just last year from imaging studies that suggested dopamine-glutamate interactions play a role in schizophrenia. They may indeed play a role somehow, but the newer study between Imperial College and GSK found that the genes for dopamine acted no differently in their sample from patients with schizophrenia compared to controls.
Another theory has been that the coating around nerve cells, which is made of myelin, is damaged in people with schizophrenia, but this study also found no difference in myelin genes between schizophrenic patients and control patients.