BioWorld International Correspondent
LONDON Genes whose products play a role in cholesterol and lipid transport are expressed to a significantly higher degree in the brains of people who suffer from schizophrenia, an international team of researchers and clinicians showed.
Using new technology that allows scientists to screen up to tens of thousands of genes at a time and check their activity in people with a particular disease, a group based in Cambridge, UK, together with collaborators in New Zealand, Japan and Spain, have shown that several apolipoprotein L (apo L) genes are significantly more active in schizophrenia brains than in brains of healthy individuals.
Sabine Bahn, a clinical lecturer in psychiatry at the University of Cambridge, told BioWorld International: “Using new high-density array technology, we found that the genes encoding the proteins known as apo L1 and apo L2 are consistently up-regulated in the schizophrenia brains. We don’t know the exact function of these proteins but all apolipoproteins are involved in the transport of triglycerides and cholesterol, which are the building blocks of myelin, an important component of brain white matter and essential to assure normal nerve cell function. Furthermore, apo L3 is thought to be involved in mediating inflammatory processes.”
The finding is reported in the March 12, 2002, issue of Proceedings of the National Academy of Sciences in a paper titled “Gene expression analysis in schizophrenia: Reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22.” Bahn said the finding fit well with work reported last year by another team of researchers, which found that a group of myelin-related genes were all down-regulated in schizophrenia.
The Stanley Foundation, a nonprofit organization in Baltimore that supports research on the causes and treatment of schizophrenia and bipolar disorder, recently awarded Bahn generous support to continue and extend her work.
For the study reported in PNAS, Bahn and her colleagues used samples of post-mortem brain tissue provided by the Stanley Foundation obtained from 15 schizophrenia sufferers, as well as from 15 bipolar disorder sufferers, 15 with major depression, and 15 normal controls.
Bahn then chose about 300 genes that she thought might play a role in schizophrenia. She selected genes that other studies had implicated in the disease; genes encoding receptors for neurotransmitters such as dopamine and serotonin; genes known to be involved in apoptosis, inflammation and viral infection; and, finally, genes that were known to reside in chromosomal loci that have been linked to schizophrenia.
“We were already interested in the apolipoprotein genes because of the link of apolipoprotein E with Alzheimer’s disease and because apo L genes are located on a high-susceptibility locus,” Bahn said.
Having obtained the complementary DNA for all the genes they wanted to study, the group set these out in an array. They then extracted messenger RNA from the post-mortem tissue samples, and reverse-transcribed this to make complementary DNA, using a radioactively labeled component. The complementary DNA made in this way was used as a probe and hybridized to the DNA comprising the gene array. The researchers then looked to see whether there was a difference in the hybridization patterns between the probes derived from schizophrenia brains and those derived from control brains.
The results, said Bahn, were “very significant. We got about 15 genes that were differentially expressed. We found that apo L1 was significantly up-regulated particularly consistently.” Further experiments also confirmed the result.
Having discovered that there was a whole cluster of apo L genes, in addition to the one on the array, the researchers decided to investigate the expression of the others. “One of these has already been shown to be up-regulated in inflammatory processes, and we found that altogether three genes in this cluster were highly up-regulated in the schizophrenia brains,” Bahn said.
They then set out to cross-validate the first part of their study by examining the expression of apo L1 and apo L2 in a further independent set of schizophrenia brains 20 from New Zealand and 20 from Japan. Their initial finding held up.
The group now is planning to collaborate with researchers in London with access to other collections of brain tissue, to find out whether they, too, can detect differences in expression of apo L1 and apo L2 between people who had schizophrenia and those who did not.
Bahn also is planning a collaborative study with Peter Jones, head of the department of psychiatry at the University of Cambridge and a specialist in epidemiology. They plan to obtain blood samples from all people newly diagnosed with schizophrenia in East Anglia (a region of Eastern England). Thousands of samples could be gathered in this way and tested for differences in the expression of genes in peripheral blood. Ultimately, Bahn said, such differences could possibly be used as a diagnostic tool.