Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder
Autor: | Jessica F. Hoffman, Allison Goff, Peter Schmidt, David Goldman, Neelima Dubey, David R. Rubinow, Maria Mazzu, Yonwoo Jung, Dion Hipolito, Howard J. Li, Sarah Rudzinskas |
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Rok vydání: | 2021 |
Předmět: |
Cell biology
medicine.medical_specialty XBP1 Thapsigargin media_common.quotation_subject Biology Article Cellular and Molecular Neuroscience chemistry.chemical_compound Internal medicine Genetics medicine Homeostasis Humans Molecular Biology Progesterone Menstrual cycle media_common Estradiol Endoplasmic reticulum Endoplasmic Reticulum Stress medicine.disease Psychiatry and Mental health Endocrinology chemistry Unfolded protein response Female Psychiatric disorders Premenstrual Dysphoric Disorder Premenstrual dysphoric disorder Neuroscience Hormone |
Zdroj: | Molecular Psychiatry |
ISSN: | 1476-5578 1359-4184 |
Popis: | Premenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients’ differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca2+ and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca2+ homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca2+ dynamics and ER stress may contribute to the pathophysiology of PMDD. |
Databáze: | OpenAIRE |
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