Researchers close in on a molecular target for schizophrenia

Schizophrenia, one of the most common mental disorders, is still poorly understood and rarely treated with success. Offering the silver lining of a molecular target that might be addressed pharmaceutically, researchers in the US have now shown that the gene DISC1 (for Disrupted In SChizophrenia), which was originally identified in connection with schizophrenia susceptibility running in a Scottish family, is more generally associated with mental disorders, and that a variant of the DISC1 protein accumulates in the nuclei of patients’ brain cells.

Researchers at the NIH in Rockville have conducted association and linkage studies showing that DISC1 is involved in susceptibility for schizophrenia in different populations.1 Meanwhile, Akira Sawa, assistant professor of psychiatry at Johns Hopkins University, Maryland, and colleagues tracked down the corresponding protein in brain samples from deceased patients with or without mental disorders using antibody technology. They found out that most of the gene product occurs as a shorter, edited protein of around 80kDa, with only a small fraction of the full length 95-100kDa protein.2

While the total concentration of the major, 80kDa protein in brain cells is independent of mental illness, its localisation within the cells showed interesting differences.

In brains with schizophrenia and major depression, but not with bipolar disorder, the protein appears to be enriched in the cell’s nucleus in comparison with the cytoplasm, where it is known to associate with the cytoskeleton. Sawa’s group thinks that the loss of a cytoplasmic function of the protein is important in mental illness and is currently trying to work out its function.

Sub-grouping of schizophrenia into genetic subtypes may help tailor medication, he says. Moreover, ’understanding of pathogenesis at molecular levels usually leads to drugs that ameliorate disorder’.

Michael Gross

1 C A Hodgkinson et al, Am. J. Hum. Genet. 2004, 75, 862

2 N Sawamura et al, Proc. Natl. Acad. Sci. USA, 2005, 102, 1187