Healthy people who carry a particular variant of the dopamine transporter gene, the nine repeat allele, have significantly higher levels of dopamine transporter in the brain, said the lead author, Christopher van Dyck, M.D., associate professor of psychiatry and neurobiology and director of the Alzheimer ™s Disease Research Unit and the Cognitive Disorders Clinic in the Department of Psychiatry.

The new study included 96 healthy European Americans ”54 men and 42 women ”who underwent a clinical examination to exclude any neurological or psychiatric disease, alcohol abuse or substance abuse. The levels of dopamine transporter availability were measured using SPECT imaging, and the dopamine transporter genotypes were determined by co “author Joel Gelernter, M.D.

We are not yet sure if the effects of the variant on transporter levels in our healthy subjects can be generalized to neuropsychiatric disorders, van Dyck said. If they can be, our results may be relevant for substance abuse, tobacco smoking, and ADHD. The results suggest that the mechanism of association of this gene with several disorders could be altered levels of central dopamine transporter protein, influencing concentrations of extracellular dopamine.

This study replicated and expanded on a preliminary report by Leslie Jacobsen, M.D., and colleagues at Yale, although other studies of the effects of this variation on the availability of the dopamine transporter have yielded contradictory results.

In addition to Jacobsen and Gelernter, co “authors included Robert Malison, M.D., John Seibyl, M.D., Julie Staley, Marc Laruelle, M.D., Ronald Baldwin, and Robert Innis, M.D. The study was supported by grants and funds from the American Federation for Aging Research; Rose and Philip Hoffer; the Department of Veterans Affairs; the National Institute of Mental Health, and the National Institute on Drug Abuse.

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The finding of ATF2 ™s novel function in DNA repair was serendipitous. As Shoichi Takahashi, a postgraduate researcher, was testing for the changes in ATF2 in human cancers, he lost the signal for ATF2. Later, Dr. Ronai said, we did experiments that showed the signal was lost because a protein kinase, ATM, modified ATF2 enough to interfere with detection of the ATF2 signal. Soon, work performed by Anindita Bhoumik confirmed that ATF2 is regulated by ATM and that this regulation is central to the cell ™s ability to initiate DNA repair processes following ionizing irradiation or other exposures that cause breaks in DNA. A likely way in which ATF2 works is to halt the cell ™s cycle to allow repair of damaged DNA before such damage becomes permanent.

Ronai and his colleagues are now determining how molecules like ATF2 can balance their dual roles. High doses of radiation, as well as changes that take place in cancer and pathologic situations, can activate both functions of ATF2, which is expected to disturb the otherwise conserved balance between its role in gene regulation and the DNA damage response. We need to find out which of the two functions is more dominant under these circumstances in order to devise ways to regain the proper balance, he said.

The Ronai lab ™s work on ATF2 was started at Mount Sinai School of Medicine in New York City, from which Dr Ronai and his colleagues recently relocated to the Burnham Institute. This study was carried out in collaboration with Wolfgang Breitweiser and Nic Jones of the Paterson Institute for Cancer Research, Manchester, England, and Yosef Shiloh, of Tel Aviv University, Israel. The study was supported by a grant from the National Institutes of Health.

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