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Published on: September 15, 2018
Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice
Lalit Kaurani1, Md Rezaul Islam2, Urs Heilbronner3
1Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Goettingen, 37077, Göttingen, Germany. lalit.kaurani@dzne.de.
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.
Insights
This study reveals a new microRNA-99b-5p pathway involving Z-DNA binding protein 1 (Zbp1) in microglia. Reduced miR-99b-5p levels in schizophrenia patients may drive disease pathology via this pathway.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Schizophrenia treatment primarily targets protein-coding genes, overlooking microRNAs.
- MicroRNAs play crucial roles in gene regulation and cellular processes.
Purpose of the Study:
- To investigate the role of microRNAs in schizophrenia pathogenesis.
- To identify specific microRNAs dysregulated in schizophrenia patients.
- To elucidate the molecular mechanisms underlying microRNA involvement.
Main Methods:
- Analysis of microRNAome in blood and postmortem brain tissue from schizophrenia patients.
- Induction of schizophrenia-like phenotypes in mice by manipulating miR-99b-5p levels.
- Identification of Z-DNA binding protein 1 (Zbp1) as a direct target of miR-99b-5p.
- Assessment of therapeutic potential using antisense oligonucleotides against Zbp1.
Main Results:
- miR-99b-5p expression is significantly downregulated in the prefrontal cortex and blood of schizophrenia patients.
- Reduced miR-99b-5p in mice induced schizophrenia-like behaviors and microglial inflammation linked to synaptic pruning.
- Zbp1 was identified as a novel target of miR-99b-5p, mediating the inflammatory response in microglia.
- Antisense oligonucleotides targeting Zbp1 alleviated pathological effects.
Conclusions:
- A novel microglial pathway involving miR-99b-5p and Zbp1 contributes to schizophrenia pathogenesis.
- This pathway represents a potential therapeutic target for schizophrenia treatment.
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