The intracellular plasticity of mitochondria, the endoplasmic reticulum and their interplay in schizophrenia and bipolar disorder

线粒体、内质网的细胞内可塑性及其在精神分裂症和双相情感障碍中的相互作用

• 批准号: 424986253
• 负责人: Dr. Magdalena Vater
• 金额: --
• 依托单位: Center for Genomic Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/424986253?language=en
• 关键词: intracellular; plasticity; mitochondria; endoplasmic; reticulum

Bipolar disorder (BPD) and schizophrenia (SCZ) are common, highly complex and still difficult to treat psychiatric disorders sharing overlapping clinical features and genetic risk factors. A careful characterization of the disease biology at multiple levels is a prerequisite to proceed with the identification of disease-specific targets and the development of novel and personalized treatment strategies. Multiple lines of evidence suggest the existence of mitochondrial deficits in BPD and SCZ. Since studies in BPD and SCZ show disturbances in multiple crucial cellular functions i.e. calcium homeostasis known to be mediated by highly specialized mitochondria associated endoplasmic reticulum (ER) membranes (MAMs), we hypothesize that there will be disease-specific deficits in the interaction of mitochondria with the ER in neurons differentiated from induced pluripotent stem cells (iPSCs) of subjects with BPD and SCZ. We will address the following three interrelated aims using cortical neurons differentiated from iPSCs of subjects with BPD and SCZ:Aim 1: We will characterize the distribution and morphology of mitochondria and ER in iPSC-derived cortical neurons and quantify MAMs. We will study functional implications of differences in MAMs through analysis of intracellular calcium homeostasis.Aim 2: We will delineate the effects of specific perturbations on mitochondrial and ER dynamics and on the functionality of MAMs, specifically in the setting of cellular stress induced by H2O2 and hydrocortisone as well as in the presence of representative psychopharmacological compounds comprising clozapine, haloperidol, risperidone, lamotrigine and lithium. By profiling the effects of the cellular stressors and annotated small molecules on the patient-derived neurons, we will determine the disease-specific differences that are unmasked in the setting of the perturbations.Aim 3: We will test our hypothesis that GSK3-ß is involved in loosening of two MAM tethers (VAPB and PTPIP51) in BPD and SCZ, consistent with the growing evidence for dysregulation of the Wnt/GSK3ß pathway in the pathogenesis of these disorders. Therefore, we will identify cellular phosphosignaling signatures in our cellular disease models by applying the P100 “reduced-representation“ phosphoproteomic analysis to dissect the mechanistic underpinnings of the differences in the mitochondrial and ER dynamics.Successful completion of these aims will result in the identification of disease-specific differences in the morphology and distribution of mitochondria and MAMs in BPD and SCZ as well as the delineation of specific ways in which the disease neurons respond to cellular stress. The studies will also provide insights into signaling pathways that are aberrant in BPD and SCZ, at baseline and in the setting of specific perturbations. These results will lay the foundation for the development of assays for the discovery of novel small molecules that modulate the disease signatures.

双相情感障碍（BPD）和精神分裂症（SCZ）是常见的、高度复杂的、仍然难以治疗的精神疾病，它们具有重叠的临床特征和遗传风险因素。在多个层面上仔细表征疾病生物学是确定疾病特异性靶点和开发新的个性化治疗策略的先决条件。多项证据表明BPD和SCZ存在线粒体缺陷。由于BPD和SCZ的研究显示多种关键细胞功能受到干扰，例如钙稳态已知是由高度特化的线粒体相关内质网（ER）膜（MAMs）介导的，我们假设在BPD和SCZ受试者诱导多能干细胞（iPSCs）分化的神经元中，线粒体与内质网的相互作用将存在疾病特异性缺陷。我们将利用从BPD和SCZ受试者的ipsc分化的皮质神经元来解决以下三个相互关联的目标：目标1：我们将表征ipsc衍生的皮质神经元中线粒体和内质网的分布和形态，并量化MAMs。我们将通过分析细胞内钙稳态来研究MAMs差异的功能含义。目标2：我们将描述特定扰动对线粒体和内质网动力学以及MAMs功能的影响，特别是在H2O2和氢化可的松诱导的细胞应激环境中，以及在含有氯氮平、氟哌啶醇、利培酮、拉莫三嗪和锂的代表性精神药理学化合物存在的情况下。通过分析细胞应激源和注释小分子对患者源性神经元的影响，我们将确定在扰动设置中未被掩盖的疾病特异性差异。目的3：我们将验证我们的假设，即GSK3-ß参与BPD和SCZ中两个MAM系索（VAPB和PTPIP51）的松动，这与越来越多的证据表明Wnt/GSK3 -ß通路在这些疾病的发病机制中的失调一致。因此，我们将通过应用P100“减少表征”磷蛋白质组学分析来识别细胞疾病模型中的细胞磷信号信号特征，以剖析线粒体和内质网动力学差异的机制基础。成功完成这些目标将导致确定BPD和SCZ中线粒体和MAMs的形态和分布的疾病特异性差异，以及描述疾病神经元对细胞应激反应的特定方式。这些研究还将深入了解BPD和SCZ在基线和特定扰动环境下的异常信号通路。这些结果将为开发用于发现调节疾病特征的新型小分子的检测方法奠定基础。