Bipolar disorder is the sixth leading cause of disability in the world (WHO, 2006); however, the etiological basis, pathogenesis, and neurocircuitry of bipolar disorder are still poorly understood. Individuals with bipolar disorder are most often treated with the mood stabilizer lithium (Li+). (Pan J, 2011) Nevertheless, only 40% to 50% of patients respond to Li+ treatment. (DBSA, 2006) Li+ has been shown to directly inhibit Glycogen Synthase Kinase 3 (GSK-3). This inhibition is thought to lead to β-catenin accumulation in the cell, and increase the function of TCF/LEF target genes in the Wnt signaling pathway. Increased activity in this protein network stabilizes the mood of patients with bipolar disorder. (Pan J, 2011) This study primarily sought to quantify the levels of β-catenin in cells treated with Li+ or GSK-3 small-molecule inhibitors to reveal the relationship between β-catenin stabilization and GSK-3 inhibition. We found that Li+ treatment does inhibit GSK-3 in cellular models, leading to β-catenin accumulation. This effect was even more pronounced when cells were treated with potent small-molecule inhibitors of GSK-3. We provide evidence that small-molecule inhibitors of GSK-3 may potentially be used as alternative therapeutics to Li+ treatments in patients suffering from bipolar disorder.
PROJECT: Using ELISA to Quantify β-Catenin Levels by GSK-3β Inhibition in HEK293T Cells
Mentors: Jen Pan, Joshua Ketterman, Psychiatric Disease Program
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