Indexing (document details) - schizophreniastudies

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Disruption of Gene Interaction Linked to
Schizophrenia

PR Newswire
. New York:
Dec 1, 2005
. pg. 1

Abstract (Summary)

The study's findings linked changes seen at the molecular level directly to symptoms of
schizophre
nia

seen in humans, said Zakharenko, who is a co
-

author of a report on this work that
appears in the November 15 issue of Nature Neuroscience. The work was completed by
Zakharenko and his colleagues at Columbia University (New York), Rockefeller Universit
y
(New York) and the University of Utrecht (the Netherlands). Zakharenko is continuing his work
on the molecular causes of
schizophrenia

at St. Jude.

The key finding in the current study was that the models of PRODH deficiency had increased
COMT activity i
n the frontal cortex of the brain. "This might reflect a response to the increased
dopamine

activity caused by PRODH deficiency," Zakharenko said. "And it shows that when
PRODH is lost, the additional loss of COMT due to the 22q11 mutation may worsen the
s
ymptoms of
schizophrenia

by allowing
dopamine

levels to rise."

The study also showed why patients with
schizophrenia

who also have the 22q11 microdeletion
are especially disadvantaged. "COMT upregulation appears to be a response that brings the level
of
dopamine

signaling back to normal," Zakharenko said. "So patients with the 22q11
microdeletion are unable to compensate for their PRODH deficiency by upregulating COMT."


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Copyright PR Newswire Association LLC Dec 1, 2005

Studies of PRODH deficiency demonstrate COMT compensat
es for overactive

dopamine signaling, according to St. Jude

MEMPHIS, Tenn., Dec. 1 /PRNewswire/
--

The loss of the genes PRODH and COMT
contributes directly to major symptoms of schizophrenia by upsetting the balance of the brain
chemicals glutamate and
dopamine, according to a group of investigators that includes a scientist
now at St. Jude Children's Research Hospital.

A mutation that eliminates PRODH causes an abnormal rise in the levels of both of these
chemicals; the additional loss of COMT blocks th
e brain's ability to compensate for this
imbalance. This finding offers new insights into the genetic basis of schizophrenia, the
researchers said.

Schizophrenia is a mental disorder usually characterized by loss of touch with reality; illogical
thinking;
hallucinations; and other abnormal emotional, behavioral or intellectual disturbances.
The investigators developed a model of schizophrenia that provides a way to study and
understand how the loss of PRODH and COMT gene activity contributes to schizophreni
a
symptoms.

The new insights are important because the loss of the PRODH gene causes the imbalance in the
levels of both glutamate and dopamine; this imbalance contributes directly to the symptoms of
schizophrenia, according to Stanislav Zakharenko, M.D.,
Ph.D., an assistant member of the
Department of Developmental Neurobiology at St. Jude.

The team investigated the roles of PRODH and COMT because these genes are located in the
q11 region of human chromosome 22. Previous work by other scientists had showed

that a
mutation in this region
-

-

the 22q11 microdeletion
--

is an important risk factor for developing
schizophrenia.

The study's findings linked changes seen at the molecular level directly to symptoms of
schizophrenia seen in humans, said Zakharenko,
who is a co
-

author of a report on this work that
appears in the November 15 issue of Nature Neuroscience. The work was completed by
Zakharenko and his colleagues at Columbia University (New York), Rockefeller University
(New York) and the University of Ut
recht (the Netherlands). Zakharenko is continuing his work
on the molecular causes of schizophrenia at St. Jude.

The key finding in the current study was that the models of PRODH deficiency had increased
COMT activity in the frontal cortex of the brain. "T
his might reflect a response to the increased
dopamine activity caused by PRODH deficiency," Zakharenko said. "And it shows that when
PRODH is lost, the additional loss of COMT due to the 22q11 mutation may worsen the
symptoms of schizophrenia by allowing
dopamine levels to rise."

The study also showed why patients with schizophrenia who also have the 22q11 microdeletion
are especially disadvantaged. "COMT upregulation appears to be a response that brings the level
of dopamine signaling back to normal," Zak
harenko said. "So patients with the 22q11
microdeletion are unable to compensate for their PRODH deficiency by upregulating COMT."

In the same issue of Nature Neuroscience, another group of investigators reports that their study
of adolescents with the 22q
11 deletion showed that low activity of COMT is a risk factor for loss
of volume of the prefrontal cortex; and that this same mutation also puts adolescents at risk for
developing psychotic symptoms.

Other authors of the study include Joseph A. Gogos, Mari
a Karayiorgou, Marta Paterlini, Wen
-
Sung Lai, Jie Qin, Hui Zhang, Jun Mukai, David Sulzer, Paul Pavlidis and Steven A. Siegelbaum
(Columbia University and Rockefeller University) and Koen G.C. Westphal and Berend Olivier
(University of Utrecht).

St. Jude C
hildren's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in
finding cures and saving children with cancer and other catastrophic diseases. Founded by late
entertainer Danny Thomas and based in
Memphis, Tennessee, St. Jude freely shares its
discoveries with scientific and medical communities around the world. No family ever pays for
treatments not covered by insurance, and families without insurance are never asked to pay. St.
Jude is financially

supported by ALSAC, its fundraising organization. For more information,
please visit www.stjude.org. SOURCE St. Jude Children's Research Hospital

[Reference]

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Indexing (document details)

Companies:

St Jude Childrens Research Hospital
-
Memphis TN

(
NAICS:

622110

)

Dateline:

Tennessee

Publication title:

PR Newswire
.

New York:

Dec 1, 2005
.


pg. 1

Source type:

Wire Feed

ProQuest
document ID:

934569131

Text Word
Count

663

Document URL:

http://proquest.umi.com/pqdweb?did=934569131&sid=2&Fmt=3&clientId=
5355&RQT=309&VName=PQD