Advances in science require collaboration, innovation and a lot of painstaking hard work. An ongoing research project at the University of North Carolina-Chapel Hill that studies the possible genetic causes of schizophrenia is no exception.
The work, led by UNC Professor of Psychiatry Diana Perkins, includes collaboration among researchers in psychiatry, biostatistics, biochemistry, and cell biology; innovative analysis tools and technical expertise from the Renaissance Computing Institute (RENCI); and methodical, sometimes frustrating, hard work from all.
But the work is paying off: in a study published in the online version of the journal Genome Biology, the research team announced they may have identified a molecular mechanism underlying the development of schizophrenia. This controlling mechanism, says Clark Jeffries, a RENCI biosciences research professor and one of the co-authors of the paper, could be an important first step to understanding the causes of schizophrenia and developing better treatments.
“A lot more research needs to be done and a much better understanding of the biochemistry involved is needed,” says Jeffries, who is also a professor in the UNC School of Pharmacy. “But this is a start and it is an approach that hasn’t been tried until now.”
In studying the postmortem brain tissue of adults who had been diagnosed with schizophrenia, the researchers found that levels of gene-regulating molecules called microRNAs were lower among schizophrenia patients than in persons who were free of psychiatric illness.
MicroRNA molecules were first discovered in the cells of the roundworm C. elegans in the early 1990s. Since then, they have been found in many forms in many species. Presently scientists believe that more than 450 microRNAs might have roles in regulating thousands of human genes.
While these tiny strands of ribonucleic acid do not carry the code for a protein, by binding to matching pieces of messenger RNA they delay or stop translation of mRNA. When a cell needs certain proteins, the microRNAs disconnect, thus allowing protein expression to resume.
“In many disorders, gene mutations cause malformed proteins. But with some complex diseases – schizophrenia, heart disease, dementias – we find not mutated proteins, but correctly formed proteins in incorrect amounts,” said Perkins.
Previous studies have shown that miRNAs play a role in regulating brain development. They also figure importantly in “synaptic plasticity,” the ability of neurons to make connections with one another. “And those connections come and go all the time. It’s a normal process for them to be pruned and grow again, depending on what the brain needs to do to interact with the environment,” Perkins explained. “We think schizophrenia may be a disorder of the synapse.”
Using postmortem brain tissue of people with schizophrenia and persons who had no psychiatric illness, the researchers found for the first time a significant difference in the expression profile of 16 particular microRNAs; 15 of the 16 were expressed at a lower level in the prefrontal cortex of people with schizophrenia. The basic activity of this “executive” brain region is the orchestration of thoughts and actions in accordance with internal goals.
The research team arrived at their conclusions with analytical help provided by RENCI and Jeffries. First, RENCI used its computational resources to analyze tissue microarrays that looked for differences in the tissue from healthy and schizophrenic persons. The team looked for differences that were consistent across the tissue samples, since these are likely to indicate a pattern, rather than a simple random difference, said Jeffries.
The molecular differences they found in 15 of the 16 schizophrenia samples were consistent, but small. To further confirm the research team’s results, RENCI helped with another analysis of the tissue samples, called PCR, or polymerase chain reaction. Often used to identify the genetic markers of disease, PCR exponentially amplifies a strand of DNA—the way a living cell would—without using a living organism. PCR gives researchers a larger study sample, and PCR tests on the brain tissue samples provided the same results as the microarray analysis, said Jeffries.
RENCI also analyzed motifs, or patterns within the DNA of the tissue samples, in an effort to find the common central mechanism that could be triggering the differences in microRNA expression.
“We are looking to answer the question ‘What signals all these complex changes?’ We want to find out how nature turns all those knobs and makes all those changes at the molecular level,” explained Jeffries. “If we can find the common control mechanism, we can begin to find the real cause of this disease.”
Added Perkins, “Our study found a striking, significant difference in microRNA expression between people with schizophrenia and healthy people. Using bioinformatic analyses we found that the distinguished microRNAs are predicted to regulate genes involved in synaptic plasticity.”
According to the authors, the study is the first to associate altered expression of miRNAs with schizophrenia, a disease that affects 1 in every 100 people worldwide.
Acknowledging this was a pilot study, Perkins, Jeffries and their colleagues plan further research with larger tissue samples. And RENCI will continue to play the role of enabler, bringing innovative analysis tools and discovery tools to bear on a disease that is often misunderstood and misdiagnosed.
