ACHEMS 2019
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SPLTRAK Abstract Submission
Altered dynamics of glucocorticoid receptor – chaperone complexes in neuroepithelial cells of patients with depression
Karin Borgmann-Winter1,2, Sarah Jefferson1, John O'Reardon1, Nancy Rawson3, Olivier Berton1, Chang-Gyu Hahn1
1University of Pennsylvania, Philadelphia, PA, United States
2Children's Hospital of Philadelphia, Philadelphia, PA, United States
3Monell Chemical Senses Center, Philadelphia, PA, United States

Background: As the only neural cell type available from living individuals without genomic reprogramming, olfactory neuroepithelial cells represent a uniquely valuable tool to dissect the molecular pathophysiology of neuropsychiatric disorders. Our laboratory has previously used these cells in studies of bipolar disorder and schizophrenia (Borgmann-Winter 2015, 2016)   Objective: To examine molecular alterations in glucocorticoid receptor (GR) chaperone complex dynamics in the pathophysiology of major depressive disorder (MDD)   Method: We examined GR – chaperone interactions in olfactory neuroepithelial cells derived from 15 matched pairs of MDD subjects and healthy controls for nuclear translocation of glucocorticoid receptor (GR translocation), GR-chaperone interactions and their inter-relationships.  Results: GR translocation, a key step for glucocorticoid signaling, was strikingly reduced in the MDD group compared to control. This is not due to dysregulation of the expression of the glucocorticoid receptor or its chaperones at the mRNA or protein levels in the patient group. Interestingly protein interactions of GRs with FKBP51, which serves as a negative regulator of glucocorticoid signaling, were increased in the MDD group. In healthy subjects, FKBP51 in GR complexes showed a robust and positive correlation with GR translocation (R2= 0.88), suggesting a homeostatic balance between the two parameters. MDD subjects showed no significant correlation between FKBP51 and GR translocation.  Conclusion: These results provide the first direct evidence for dysregulated GR translocation and GR-chaperone interactions in neural cells of MDD subjects. This study indicates that OE cells derived from patients with neuropsychiatric illnesses can serve as a cellular model to study associated stress signaling.