Researchers have discovered that microRNAs — tiny molecules aiding in gene expression — are under-expressed in the brains of patients with schizophrenia. One of these molecules, known as miR-9, was found to be a key player in the risk for the disease. This particular molecule controls the activity of hundreds of genes.
The researchers discovered that miR-9 was significantly under-expressed in cells of four schizophrenic patients, compared to six control participants. The findings were also replicated in a larger sample of ten childhood-onset schizophrenic patients and ten controls.
“Schizophrenia is a very complex disorder that is believed to be strongly genetically influenced — there are probably more than 1,000 genes contributing to its development, some or many of which will affect individual patients,” said lead co-author Kristen Brennand, Ph.D., Assistant Professor of Psychiatry, Icahn School of Medicine at Mount Sinai.
“The better we are able to fill in the pieces to this very difficult puzzle, the more we can think about treatment, and, better yet, prevention.”
The genes controlled by miR-9 appear to play a role in the fetal development of neurons as well as deciding where these neurons will eventually settle in the brain. If these genes are not as active as they should be, the brain will likely be miswired, suggest the researchers.
Recent research also suggests that many genes found to be linked to schizophrenia tend to be genes that are expressed during fetal development — even though schizophrenia usually becomes symptomatic in adulthood.
“The idea that children are born with schizophrenia should take the pressure off of parents,” said Brennand. “This is a heritable disease that runs in families, and it’s no one’s fault that someone was born with this genetic risk.”
The slow progress in decoding schizophrenia comes from the lack of live brain tissue to study. In this study, the research team pioneered a new approach that combined expertise in stem cell biology, neurobiology, genomics, and systems biology. They took skin samples from patients, reprogrammed them into induced pluripotent stem cells, and then differentiated these cells into precise subtypes of human neurons.
“This has allowed us to begin to ask how and why neurons derived from schizophrenia patients differ from those derived from people who are unaffected by the disorder,” said Brennand.
“The goal of our research is to not just understand the genetic mechanisms contributing to schizophrenia, but ultimately to develop a screening platform that we can use to identify new therapeutics for the treatment of this debilitating disorder.”
The researchers ran into some unique challenges at the beginning of the project in that “miR-9 was not the only miRNA that is differentially expressed in cells from schizophrenia patients compared to control participants,” said lead co-author Gang Fang PhD, an Assistant Professor in the Department of Genetics and Genomic Sciences.
“In fact, tens of miRNAs reached statistical significance and we wanted to identify a smaller number of key players. We took a systems biology approach, where we integrated miRNA expression, gene expression, global gene regulatory networks, and proteomic data.”
“This approach found evidence suggesting miR-9 has the most significant change of regulatory activity in addition to the expression change of itself,” said Fang. “We hope this general approach will also help the discovery of additional genetic regulators of schizophrenia and other diseases.”
The researchers highlight that their new findings confirm the results of an earlier study published March 9 in JAMA Psychiatry, in which a genetic screen, taken from the blood of 35,000 schizophrenia patients, found either low expression or mutations in the hundreds of genes that miR-9 controls.
The new study is published online in the journal Cell Reports.
Source: Mount Sinai Hospital