Studies of PRODH deficiency demonstrate COMT compensates 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 the 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 schizophrenia 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 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 in 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 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," Zakharenko 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 22q11 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, Maria 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 Children'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 http://www.stjude.org/.
CONTACT: Carrie Strehlau of St. Jude Public Relations, +1-901-495-2295, or carrie.strehlau@stjude.org, or Marc Kusinitz of St. Jude Scientific Communications, +1-901-495-5020, or marc.kusinitz@stjude.org
Web site: http://www.stjude.org/
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