Researchers have proposed that abnormalities in a nervous-system protein known as DISC1 might be a cause of many cases of schizophrenia, bipolar disorder and depression.
In the April 9 Journal of Neuroscience, researchers from Heinrich Heine University in Germany and the University of Santiago de Compostela in Spain reported finding insoluble aggregates of DISC1 in 20 percent of postmortem brain samples from people who had been diagnosed with schizophrenia, depression and bipolar disorder. The researchers did not find such aggregates in control samples from people who had not been diagnosed with such a disorder.
The researchers also produced an insoluble form of DISC1 by over-expressing its gene in test cells and showed that in this apparently abnormal form, DISC1 fails to bind to another protein regarded as an important signaling partner.
“We think the insoluble form of DISC1 might fail to interact properly with key signal transmitting molecules,” says Carsten Korth, principal investigator for the study. “We’re looking into the possibility that it also actively disturbs biological circuits relevant to chronic mental diseases.”
In the past two decades, DISC1 has become a target of widespread research into the factors that can cause these disorders. In 1990, researchers from the University of Edinburgh studying a large, mental-illness-prone Scottish family found that schizophrenia and other psychiatric diagnoses were associated with a specific chromosomal abnormality. The abnormality is a “translocation” error, involving the switch of one segment of DNA from chromosome 1 to 11, with the displaced chromosome 11 segment splicing into chromosome 1. Another University of Edinburgh group reported in 2000 and 2001 that this mutation truncated a chromosome 1 gene, which they sequenced and named DISC1 (“Disrupted In Schizophrenia–1”).
Subsequent studies in several other populations have tied schizophrenia and other mental disorders to seemingly rare mutations in DISC1. Mice with mutant DISC1 also show mental abnormalities, including social withdrawal and impaired working memory. In the past few years, studies of DISC1’s protein product, which is produced by neurons throughout the brain, have also begun to clarify what DISC1 does.
“The emerging picture is of DISC1 as a hub or scaffold protein that interacts with a very wide range of other proteins, perhaps several at any one time,” says David Porteous, who oversees the medical genetics laboratories at the University of Edinburgh. “If we inhibit the expression of DISC1 in the brain of the mouse, either very early in development or late in development, then we alter the normal pattern of neurogenesis and of neuronal migration. We believe that it may be playing an important role, among others, in synaptic pruning and also in neuronal connectivity. And that fits rather nicely with the long-standing concept of schizophrenia as a neurodevelopmental disorder.”
The report by Korth’s group “is a really interesting observation and one which forces us to ask a whole series of additional questions,” says Porteous. “The experimental approaches to these are going to be quite tricky, although we do now have the advantages of mouse models with abnormally expressed DISC1, and it would be very interesting to look at aged mice to see whether we can see any evidence for this.”
From familial to sporadic
In some ways, the unfolding DISC1 story fits into a broader pattern of brain disease research. “For degenerative conditions such as Alzheimer’s, Parkinson’s and prion diseases, the same gene products that are disrupted in familial cases have been demonstrated to have a role in some sporadic cases,” says Korth. “In our study we tried to make the same connection by linking the DISC1 protein to sporadic cases of chronic mental disease.”
“Whether or not DISC1 is involved in sporadic forms is still debated,” says Porteous. “But the evidence so far points to that being a reasonable probability.”
It remains to be seen whether genetic or environmental factors play a greater role in shifting DISC1 towards a dysfunctional state in the much more common sporadic forms of disease. But studies of twins, families and broad patient populations suggest that schizophrenia, bipolar disorder and unipolar depression are caused by complex interactions among both environmental and genetic factors.
“I find that the distinction between familial and sporadic isn’t very productive because the majority of the presentations which are not strictly or clearly familial will have a genetic component to them,” says Porteous.
Locating such components is now a major focus of research. But Porteous and other researchers now tend to see multiple layers of causality beneath these diseases. The primary risk factors may be largely genetic, but in many cases other, secondary factors—both genetic and environmental—may precipitate disease and determine the precise form in which it manifests. “It’s clearly going to be a very interesting challenge to understand what those precipitating agents might be,” Porteous says.