학술논문
Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice
Document Type
Original Paper
Author
Kaurani, Lalit; Islam, Md Rezaul; Heilbronner, Urs; Krüger, Dennis M; Zhou, Jiayin; Methi, Aditi; Strauss, Judith; Pradhan, Ranjit; Schröder, Sophie; Burkhardt, Susanne; Schuetz, Anna-Lena; Pena, Tonatiuh; Erlebach, Lena; Bühler, Anika; Budde, Monika; Senner, Fanny; Kohshour, Mojtaba Oraki; Schulte, Eva C; Schmauß, Max; Reininghaus, Eva Z; Juckel, Georg; Kronenberg-Versteeg, Deborah; Delalle, Ivana; Odoardi, Francesca; Flügel, Alexander; Schulze, Thomas G; Falkai, Peter; Sananbenesi, Farahnaz; Fischer, Andre
Source
The EMBO Journal. 43(8):1420-1444
Subject
Language
English
ISSN
1460-2075
Abstract
Current approaches to the treatment of schizophrenia have mainly focused on the protein-coding part of the genome; in this context, the roles of microRNAs have received less attention. In the present study, we analyze the microRNAome in the blood and postmortem brains of schizophrenia patients, showing that the expression of miR-99b-5p is downregulated in both the prefrontal cortex and blood of patients. Lowering the amount of miR-99b-5p in mice leads to both schizophrenia-like phenotypes and inflammatory processes that are linked to synaptic pruning in microglia. The microglial miR-99b-5p-supressed inflammatory response requires Z-DNA binding protein 1 (Zbp1), which we identify as a novel miR-99b-5p target. Antisense oligonucleotides against Zbp1 ameliorate the pathological effects of miR-99b-5p inhibition. Our findings indicate that a novel miR-99b-5p-Zbp1 pathway in microglia might contribute to the pathogenesis of schizophrenia.
Synopsis: The involvement of microRNAs in the pathogenesis of schizophrenia is not well-understood. This study shows that miR-99b-5p regulates Z-DNA binding protein 1 (Zbp1) to control inflammatory responses in microglia and the development of schizophrenia-like symptoms in mice.miR-99b-5p is downregulated in the blood and brains of schizophrenia patients.miR-99b-5p inhibition induces schizophrenia-like phenotypes in mice and microglial inflammation.Zbp1 is a novel miR-99b-5p target in microglia.Zbp1 antisense oligos ameliorate the pathological outcomes of decreased miR-99b-5p levels.
Dysregulation of a novel miR-99b-5p-Zbp1 (Z-DNA binding protein 1) pathway in microglia induces inflammatory responses and schizophrenia-like phenotypes in mice.
Synopsis: The involvement of microRNAs in the pathogenesis of schizophrenia is not well-understood. This study shows that miR-99b-5p regulates Z-DNA binding protein 1 (Zbp1) to control inflammatory responses in microglia and the development of schizophrenia-like symptoms in mice.miR-99b-5p is downregulated in the blood and brains of schizophrenia patients.miR-99b-5p inhibition induces schizophrenia-like phenotypes in mice and microglial inflammation.Zbp1 is a novel miR-99b-5p target in microglia.Zbp1 antisense oligos ameliorate the pathological outcomes of decreased miR-99b-5p levels.
Dysregulation of a novel miR-99b-5p-Zbp1 (Z-DNA binding protein 1) pathway in microglia induces inflammatory responses and schizophrenia-like phenotypes in mice.