A newly identified genetic pathway could lead to drugs that slow mental illness
BY JOSEPH BONNER
Over the past decade, Maria Karayiorgou and
her colleagues have narrowed the search for the genetic roots of
schizophrenia. Today, Karayiorgou’s lab is primarily focused
on two small areas on chromosomes 8 and 22 that likely harbor genes
that influence susceptibility to the mental illness.
Last year, working with scientists in the
United States and South Africa, Karayiorgou completed a systematic
scan on one of those regions and identified several individual
genes as strong candidates.
Now a recent study of over 400 families with a
history of schizophrenia confirms she’s on the right track.
After conducting genetic studies on the
families, Karayiorgou discovered that one set of genes, known as
PPP3CC and believed to code for a subunit of calcineurin, was
present in 38 percent of the parents’ chromosomes – and
was transmitted to children with schizophrenia more times than
would be expected by chance.
In another study, conducted by
Karayiorgou’s colleagues at MIT and Columbia University,
scientists looked at mice that were genetically altered to lack an
enzyme called calcineurin, which has roles in the immune system and
the brain. The result: the mice had behavioral abnormalities,
including memory impairment and social withdrawal, that were similar to those seen in people with schizophrenia.
“Based on our examination of 410
families with a history of schizophrenia and a new mouse model of
schizophrenia, we have obtained several lines of converging
evidence that show a disruption in calcineurin signaling plays a
role in the development of schizophrenia,” says Karayiorgou,
head of the Laboratory of Human Neurogenetics.
The findings illustrate why schizophrenia
researchers look not only at individual genes, but also at groups
of genes. “We are now thinking more in terms of pathways
rather than one gene at a time. Different genes in a given pathway
may be malfunctioning in different patients
with the same end result,” she explains. Based on this
hypothesis, Karayiorgou has extended her search to look at other
genes in the calcineurin pathway – and other pathways –
using genetic screening techniques.
Eventually, the research could lead to drugs
that selectively target and block the function of specific genetic
pathways that contribute to the development and progression of
schizophrenia. That would mean a better life for millions of
sufferers who have trouble with memory as well as deficits in
emotional and social behavior. About one percent of the population
worldwide is affected by the disease.