A novel miR-99b-5p- Zbp1 pathway in microglia contributes to the pathogenesis of schizophrenia
Year: 2023
Type: preprint
Abstract: Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended on Z-DNA binding protein 1 ( Zbp1 ) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p- Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy.
Authors: Lalit Kaurani, Md Rezaul Islam, Urs Heilbronner, Dennis M. Krüger, Jiayin Zhou, Aditi Methi, Judith Strauss, Ranjit Pradhan, Susanne Burkhardt, Tonatiuh Pena, Lena Erlebach, Anika Bühler, Monika Budde, Fanny Senner, Mojtaba Oraki Kohshour, Eva C. Schulte, Max Schmauß, Eva Z. Reininghaus, Georg Juckel, Deborah Kronenberg-Versteeg, Ivana Delalle, Francesca Odoardi, Alexander Flügel, Thomas G. Schulze, Peter Falkai, Farahnaz Sananbenesi, Andre Fischer
Institutions: German Center for Neurodegenerative Diseases, Institut für Psychiatrische Phänomik und Genomik, Ludwig-Maximilians-Universität München, Universitätsmedizin Göttingen, Hertie Institute for Clinical Brain Research, University of Tübingen, University of Bonn, University Hospital Bonn, University of Augsburg, Bezirkskrankenhaus Augsburg, Medical University of Graz, LWL-Universitätsklinikum Bochum, Ruhr University Bochum, Brown University, Lifespan, Multiscale Bioimaging, University of Göttingen
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G3445732291, A New Intervention for Implementation of Pharmacogenetics in Psychiatry, G434337789, G5131877326, Longitudinale Veränderungen der Gesamtheit kleiner RNAs in der transdiagnostinschen PsyCourse Studie, G584537252, EXC 2067: Multiscale Bioimaging: Von molekularen Maschinen zu Netzwerken erregbarer Zellen, Characterization of EWI-2wint and the mechanism behind its inhibition of HCV infection, G7987891391
OpenAlex ID: W4353083904