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.
The skin cells of four adults with schizophrenia have provided an
unprecedented "window" into how the disease began while they were still
in the womb, according to a recent paper in Schizophrenia Research
The paper was published online in January by researchers at the
Jacobs School of Medicine and Biomedical Sciences at the University at
Buffalo in collaboration with the Icahn School of Medicine at Mount
Sinai. It provides what the authors call the first proof of concept for
their hypothesis that a common genomic pathway lies at the root of
‘A single genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways involving more than 100 genes believed to be involved in schizophrenia.’
The 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.
Michal K. Stachowiak, senior
author on the paper, and professor in the Department of Pathology and
Anatomical Sciences in the Jacobs School of Medicine and Biomedical
Sciences at UB, said, "We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here."
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," said Stachowiak. "This work gives us an
unprecedented insight into those processes."
A central intersection point
The research provides what he 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 FGFR 1 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,"
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 said.
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 said.