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

• Applicant: Dr. Magdalena Vater
• Subject Area: Biological Psychiatry
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424986253

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Rakesh Karmacharya