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May 04, 2007
Different Damage to Same Gene (DISC1) Can Either Increase Risk for Schizophrenia or Depression
Scientists have pinpointed how different types of damage to the same gene can cause some people to suffer from schizophrenia while others develop major depression.
The researchers have demonstrated for the first time that malfunction of a gene that had been associated with schizophrenia and depression does indeed cause symptoms of those disorders. They said their findings in mice offer a possible animal model for developing treatments for schizophrenia and depression.
Steven Clapcote, David Porteous, John Roder, and colleagues, whose findings were reported in the May 3, 2007 issue of the journal Neuron, published by Cell Press, provide further evidence that these illnesses are inherited, and that the two disorders share common genetic mechanisms.
They hope that their findings may in the future help doctors pinpoint which patients will respond to different types of treatments.
Experts from the University of Edinburgh, working with researchers from Mount Sinai Hospital in Toronto, Canada and RIKEN in Japan, studied two types of damage to a gene called DISC1 "Disrupted in schizophrenia 1". They sought to explore the consequences of mutating that gene, since previous research at the University, working with families with a high incidence of mental illness, identified this gene as being linked to schizophrenia, manic depression (bipolar affective disorder) and major depression. The gene was also found to be essential for brain signaling and plays a key role in learning, memory and mood.
The researchers' theory was that different mutant variations of DISC1 might have different pathological effects. To test this theory, the researchers screened a large population of mouse mutants to isolate two with different mutations in DISC1.
They found that, indeed, one of the mutant mouse strains exhibited behavioral abnormalities and memory deficiencies resembling the symptoms of schizophrenia in humans. Additionally, these symptoms could be alleviated in the mice by antipsychotic drugs.
Similarly, the other mutant mouse strain showed behaviors that reflected depressive symptoms. These symptoms could be alleviated by an antidepressant, found the researchers.
These results show that two different types of damage to the same gene can cause different symptoms - one being symptoms of schizophrenia, and the other, of depression. The results also suggest that one responded better to antipsychotics, used to treat schizophrenia while the other responded better to anti-depressants, used to treat mood disorders.
Prof David Porteous, Chair of Human Molecular Genetics and Medicine at the University of Edinburgh, said:
"While the [exact] causes of schizophrenia, bipolar affective disorder and major depression are unknown, all the evidence points to subtle differences in the way the brain develops and to chemical changes in the brain. Our previous work identified the DISC1 gene as an important risk factor in these types of mental illness.
Both types of DISC1 mutant mice exhibited the same kind of reduced brain volume seen in people with schizophrenia and depression, the researchers found. Also, both types showed biochemical abnormalities in the function of the protein produced by the DISC1 gene.
The researchers hope that the different effects of antipsychotic and antidepressant drugs on the two mutant strains "might provide clues to effective medications for these patient groups. Indeed, these mice could represent a model system to explore novel treatment and preventative strategies for certain symptoms of major mental illness."
Clapcote and colleagues concluded:
"We have shown that two independent missense mutations in mouse DISC1 elicit distinct physiological, pharmacological, neuroanatomical, and behavioral phenotypes, which when taken together are strikingly consistent with the emerging picture from clinical and basic studies of DISC1 as a common genetic and biologically plausible risk factor for major mental illness.
This study was supported by grants-in-aid to J.C.R. from the Canadian Institutes of Health Research (CIHR; GMH-79044) and the National Alliance for Research on Schizophrenia and Depression, to Y.G. from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and to D.J.P., J.K.M., and M.D.H. from the Medical Research Council (UK). J.C.R. holds a Canada Research Chair.
Posted by Jeanie Wolfson at May 4, 2007 07:00 AM
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