Schizophrenic Brain Develops from Dysregulated Genomic Pathway

February 28, 2017
Schizophrenic Brain Develops from Dysregulated Genomic Pathway
Source: NIH

A collaboration with researchers at the Jacobs School of Medicine and Biomedical Sciences at the University of Buffalo (UB) and the Icahn School of Medicine at Mount Sinai, has produced findings supporting the hypothesis that a common genomic pathway lies at the root of schizophrenia. The results of this new study were published in Schizophrenia Research through an article entitled “Common developmental genome deprogramming in schizophrenia—Role of Integrative Nuclear FGFR1 Signaling (INFS).”

The investigators feel that their work is a first step toward the design of treatments that could be administered to pregnant mothers at high risk for bearing a child with schizophrenia, potentially preventing the disease before it begins.

“In the last ten years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease,” explained senior study investigator Michal Stachowiak, Ph.D., professor in the Department of Pathology and Anatomical Sciences in the Jacobs School of Medicine and Biomedical Sciences at UB. "We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here."

Interestingly, the researchers looked to gain insight into the early brain pathology of schizophrenia by using skin cells from four adults with the disease and four adults without—which were subsequently reprogrammed back into induced pluripotent stem cells and then into neuronal progenitor cells.

"By studying induced pluripotent stem cells developed from different patients, we recreated the process that takes place during early brain development in utero, thus obtaining an unprecedented view of how this disease develops," Dr. Stachowiak noted. "This work gives us an unprecedented insight into those processes."

In 2013, Dr. Stachowiak and his colleagues published a hypothesis proposing that a single genomic pathway, called Integrative Nuclear FGFR 1 Signaling (INFS), was a central intersection point for multiple pathways involving more than 1,000 genes believed to be involved in schizophrenia. The team believes that the results from the current study are proof of concept on their initial hypothesis.

"This research shows that there is a common dysregulated gene program that may be impacting more than 1,000 genes and that the great majority of those genes are targeted by the dysregulated nuclear FGFR1," Stachowiak said.

When even one of the many schizophrenia-linked genes undergoes mutation, by affecting the INFS, it throws off the development of the brain as a whole, similar to the way that an entire orchestra can be affected by a musician playing just one wrong note. The scientists feel the next step in their research is to use these induced pluripotent stem cells to study further how the genome becomes dysregulated, allowing the disease to develop.

"We will utilize this strategy to grow cerebral organoids—mini-brains in a sense—to determine how this genomic dysregulation affects early brain development and to test potential preventive or corrective treatments," Dr. Stachowiak concluded.