Interest in Bipolar Disorder Drug Lithium Exposes Possible Link with Splicing Factors and May Lead to Better Understanding of Leukemia Progression

A research project that began 20 years ago with an interest in how lithium treats mood disorders has yielded insights into the progression of blood cancers such as leukemia. The open-access article, which centers on a protein called GSK-3, was published online on September 15, 2017, and will be published in the November 3, 2017 issue of the Journal of Biological Chemistry. The article is titled “Phosphoproteomics Reveals That Glycogen Synthase Kinase-3 Phosphorylates Multiple Splicing Factors and Is Associated with Alternative Splicing.” Lithium is considered a highly effective treatment for bipolar disorder and other mood disorders, but it still works in only a fraction of patients and has a number of side effects. Furthermore, its mechanism of action is poorly understood, hampering efforts to improve on it. In 1996, Dr. Peter Klein of the University of Pennsylvania discovered that one of lithium's biological activities was inhibiting GSK-3, an enzyme that modifies other proteins by attaching phosphate molecules, a process called phosphorylation. Lithium's effect on GSK-3 affected the development of animal cells, but it is still unknown what connection, if any, this has to psychiatric disease. Since then, Dr. Klein, now a professor of medicine at the University of Pennsylvania, has been investigating many different aspects of GSK-3 activity. "In this paper, we were trying to find out what proteins in the cell are affected by GSK-3 inhibition," Dr. Klein said. "We compared cells with GSK-3 to cells completely lacking GSK-3 to ask how other proteins changed." "Mood disorders are so multifaceted in terms of the pathways and pathologies involved; it's really difficult to pin down a specific pathway," said Dr. Mansi Shinde, a former graduate student in Dr. Klein's research group who led the new study. "We said: Let's look at what GSK-3 does, and that would maybe lead us toward what lithium does."
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