Research Links Genomic Pathway to Schizophrenia for First Time

Senior author Michal K. Stachowiak, PhD, and fellow researchers say the 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 10 years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease,” says Stachowiak, professor of pathology and anatomical sciences.

“We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here,” he says.

The authors gained insight into the early brain pathology of schizophrenia by using skin cells — from four adults with schizophrenia and four adults without the disease — that were 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,” says Stachowiak. 

“This work gives us an unprecedented insight into those processes.”

The research provides what Stachowiak calls proof of concept for the hypothesis he and his colleagues published in 2013. They proposed that a single genomic pathway, called the Integrative Nuclear FGFR1 Signaling (INFS), is a central intersection point for multiple pathways involving more than 100 genes believed to be involved in schizophrenia.

“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 says.

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, he says.

The next step in the research is to use these induced pluripotent stem cells to further study 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,” he says.

In addition to Stachowiak, co-authors on “Common Developmental Genome Deprogramming in Schizophrenia — Role of Integrative Nuclear FGFR1 Signaling (INFS)” at UB are:

• Pinaki Sarder, PhD, and Ewa K. Stachowiak, PhD, assistant professors of pathology and anatomical sciences
• graduate students Sridhar T. Narla, Yeongwoo Lee and Courtney A. Benson

K.J. Brennand of the Icahn School of Medicine at Mt. Sinai also is a co-author.

The work is funded by NYSTEM, the Patrick P. Lee Foundation, the National Science Foundation and the National Institutes of Health.