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New Clues: Could Viruses or Myelin, the Fatty Insulation Surrounding Nerves, Play a Role in Schizophrenia?
By Bijal P. Trivedi

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Altered activity of genes involved in myelination could be the molecular signature of schizophrenia. A new study showing irregular activity of myelin-related genes in schizophrenics suggests that subtle defects in myelination during brain development might cause abnormalities leading to the disease.

Louis Wain, a 20th century artist known for his paintings of cats, painted these pictures over the period of time in which he developed schizophrenia. View larger

"This is our best guess. But this is a pretty novel finding and at this point how myelination triggers schizophrenia is just not clear," says Allen Fienberg, of the Genomics Institute of the Novartis Research Foundation in San Diego, California.

Schizophrenia doesn't leave any obvious fingerprints in the brain, so new findings about myelination, as well as a preliminary report about schizophrenia and retroviruses are creating a sense of hope among researchers in the field. The smattering of new research reveals some intriguing findings.

Fienberg's study suggests that deficiencies in myelination—the process of wrapping nerves in a fatty layer of insulation called myelin—may play a role in the disease. In the second study, genetic sequences of retroviruses have been found in individuals with early-stage schizophrenia. Some scientists are proposing that activating these viral sequences within the central nervous system may trigger the disease in some people. Both articles appear in the current issue of Proceedings of the National Academy of Sciences.

Fienberg and colleagues used DNA microarrays to survey the activity of 6,000 genes in schizophrenics. Using postmortem tissue from the dorsolateral prefrontal cortex, a region of the brain that has been implicated in the pathology of the disease, Fienberg's team found 89 genes that were regulated differently in elderly schizophrenics compared with healthy controls. Of these, 35 genes are involved in myelination.

"Each gene probe on the array is like an individual experiment. One probe on the array doesn't affect another, so pulling 35 genes that are all involved in a single process—myelination—is striking," says Fienberg. Of the myelin-related genes, six showed less expression, while the others were more active. The microarray used in this study held probes for 6,000 genes, about 20 percent of the human genome.

In myelination, oligodendrocytes, cells belonging to the central nervous system, wrap myelin around each nerve cell. Myelin insulates nerve cells, the same way plastic insulates an electrical wire, and is essential for transmitting electrical signals through the brain without interference.

"Defects in myelination may not be the primary cause of schizophrenia, but our results indicate that measuring the activity of these genes may have diagnostic applications," says Fienberg, who is now at The Rockefeller University in New York. Based solely on an activity profile of the 35 myelin-related genes, investigators correctly predicted whether a particular sample came from a schizophrenic or a control brain.

"Aside from myelin-related genes we picked up GABA, dopamine-related and some presynaptic proteins which were nice positive controls," says Fienberg. The identification of genes involved in signaling supports previous findings that imbalances in neurotransmitters, like dopamine, are associated with schizophrenia.

Researchers led by Robert Yolken, of The Johns Hopkins University School of Medicine, in Baltimore, Maryland, believe that endogenous retroviruses, which are part of the human genome, may cause schizophrenia in some individuals.

Over millions of years the human genome has acquired hundreds of thousands of viral hitchhikers.

"Most human tissues contain low levels of RNA from these endogenous retroviruses. What surprised us were the high levels of retroviral sequences in individuals with a recent onset of schizophrenia," says Yolken.

A letter-by-letter analysis of the RNA sequence suggests that one of the families of human endogenous retroviruses (HERV-W) is producing this RNA. There are between 30 and 50 HERV-W embedded in the human genome, says Yolken.

A retrovirus encodes its genome using RNA, but can rewrite its genetic code using DNA. In the DNA form, the virus can splice itself into a human chromosome and become part of the genome. Over millions of years the human genome has acquired hundreds of thousands of viral hitchhikers, but over time most of these viruses have lost essential sequences that render their genes unreadable. Conversely, a few retroviral genomes remain largely undisturbed and seem capable of producing viral proteins and possibly functional viruses.

Yolken's team found HERV-W sequences in spinal fluid from 10 of 35 individuals with a recent onset of schizophrenia. The same retroviral sequences were identified in post-mortem brain tissue from 1 of 20 chronic schizophrenics who had been ill for an average of 15 years. However, these viral sequences were absent from 22 healthy controls.

"All we can say right now is that we have found these viral sequences. Proving their role in disease requires an animal model, and we are working on this," says Yolken.

"In the ultimate clinical trial, we would give medication to suppress the transcription of endogenous retroviral elements and see whether the schizophrenic symptoms decrease or disappear. But currently there are no medications that will do this," says Yolken. In the meantime, Yolken wants to test whether suppressing viral infections, which he believes might increase the activity of HERVs, reduces symptoms in schizophrenics.

Many in the field regard Yolken's ideas as exciting but inconclusive.

"Independent replication is an axiom in all areas of medicine, but it is particularly important in studies of schizophrenia where the history of the field includes many examples of exciting findings that subsequently either failed to be confirmed in other cohorts of subjects with the disorder or proved to lack specificity to the illness," writes David Lewis, of the University of Pittsburgh, in a PNAS commentary accompanying the report on retroviral RNA and schizophrenia.

See related GNN article
»A Theory of Schizophrenia, Viruses and Pregnancy

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Hakak, Y. et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98, 4746-4751 (April 10, 2001).
Karlsson, H. et al. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci USA 98, 4634-4639 (April 10, 2001).
Lewis, D.A. Retroviruses and the pathogenesis of schizophrenia. Proc Natl Acad Sci USA 98, 4293-4294 (April 10, 2001).

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