Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Goettingen, 37077, Göttingen, Germany.
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
EMBO J. 2024 Apr;43(8):1420-1444. doi: 10.1038/s44318-024-00067-8. Epub 2024 Mar 25.
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.
目前治疗精神分裂症的方法主要集中在基因组的蛋白编码部分；在这种情况下，microRNA 的作用受到的关注较少。在本研究中，我们分析了精神分裂症患者的血液和尸检脑组织中的 microRNAome，结果表明 miR-99b-5p 在患者的前额叶皮层和血液中均表达下调。在小鼠中降低 miR-99b-5p 的含量会导致类似精神分裂症的表型和与小胶质细胞突触修剪相关的炎症过程。受 miR-99b-5p 抑制的小胶质细胞的炎症反应需要 Z-DNA 结合蛋白 1（Zbp1），我们将其鉴定为一种新的 miR-99b-5p 靶标。针对 Zbp1 的反义寡核苷酸可改善 miR-99b-5p 抑制的病理作用。我们的研究结果表明，小胶质细胞中一种新的 miR-99b-5p-Zbp1 通路可能与精神分裂症的发病机制有关。
