CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination
Open accessAbstract
Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression.
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circRNAs are abundantly expressed in the brain and are involved in the pathogenesis of neuropsychiatric disorders, impacting neuron development, cognitive function, and synaptic plasticity.
“circRNAs are abundantly expressed in the brain. And also, circRNAs are involved in the pathogenesis of neuropsychiatric disorders, impacting neuron development, cognitive function, and synaptic plasticity290–292.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [290]
The Introduction (page not provided) says circRNAs are involved in neural development and plasticity and discusses their association with Alzheimer’s disease and depression. It describes circRNAs as highly represented in the eukaryotic transcriptome, but does not specifically establish abundant expression in the brain or an impact on cognitive function. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA recent study using two different MDD mouse models demonstrated a close relationship between depression and decreased circDYM, and increased circDYM expression could significantly attenuate depressive-like behavior and inhibit microglial activity.
“a recent study using two different MDD mouse models demonstrated the presence of a close relationship between depression and decreased circDYM and revealed that increased circDYM expression could significantly attenuate depressive-like behavior and inhibit microglial activity.290”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [290]
The role of circRNAs as novel therapeutic targets to ameliorate depression-like symptoms has been demonstrated in various animal models.
“Likewise, the role of circRNAs as novel therapeutic targets to ameliorate depression-like symptoms has been demonstrated in various animal models [21][22][23][24].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
The level of circDYM was significantly lower in the peripheral blood of patients with depression and in two depressive-like mouse models induced by CUS and LPS.
“Researchers have reported that the level of circular DYM (circDYM) was significantly lower in the peripheral blood of patients with depression and in two depressive-like mouse models induced by CUS and LPS.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
circDYM acts as an endogenous miR-9 sponge to inhibit miR-9 activity, resulting in a decrease of microglial activation via HSP90 ubiquitination.
“Restoration of circDYM expression significantly attenuated depressive-like behaviors, which may have been mediated by circDYM acting as an endogenous miR-9 sponge to inhibit miR-9 activity, resulting in a decrease of microglial activation via heat shock protein 90 (HSP90) ubiquitination [21] (Fig. 3B).”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
Restoration of circDYM expression significantly attenuated depressive-like behaviors.
“Restoration of circDYM expression significantly attenuated depressive-like behaviors, which may have been mediated by circDYM acting as an endogenous miR-9 sponge to inhibit miR-9 activity, resulting in a decrease of microglial activation via heat shock protein 90 (HSP90) ubiquitination [21] (Fig. 3B).”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
CircDYM targets miR-9 to regulate microglial activation through HSP90 ubiquitination in the CUS/LPS model mouse.
“(B) CircDYM targets miR-9 to regulate microglial activation through HSP90 ubiquitination in the CUS/LPS model mouse.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
CircDYM (DYM) is downregulated in human and mouse plasma and hippocampus.
“| 23 | CircDYM | DYM | Human & | | √ | Plasma, Hippocampus | [21] |”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [21]
Circular RNA DYM (circDYM) levels are significantly decreased both in the peripheral blood of MDD patients and in the CUMS mouse models.
“Circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of MDD patients and in the CUMS mouse models.”
From Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression (2022) · cites this paper as [49]
CircDYM acts as an endogenous miR-9 sponge to restrain its activity.
“The function of CircDYM was acting as an endogenous miR-9 sponge to restrain its activity [49].”
From Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression (2022) · cites this paper as [49]
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- Authors
- Zhang, Y., Du, L., Bai, Y., Han, B., He, C., Gong, L., Huang, R., Shen, L., Chao, J., Liu, P., Zhang, H., Zhang, H., Gu, L., Li, J., Hu, G., Xie, C., Zhang, Z., & Yao, H.
- Affiliations
- Southeast University (CN)
- Zhongda Hospital Southeast University (CN)
- Henan Medical University (CN)
- Nanjing University of Chinese Medicine (CN)
- Nanjing Medical University (CN)
- Henan Psychiatric Hospital (CN)
- Corresponding author
- Xie, Chunming
- Zhang, Zhijun
- Yao, Honghong
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2018-11-09
- Volume
- 25
- Issue
- 6
- Pages
- 1175-1190
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7244405
- OpenAlex
- W2899654445
- Cited by
- 184
- References
- 63
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 27 · 2023: 29 · 2022: 27 · 2021: 34 · 2020: 19 · 2019: 5
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2017YFA0104303, 2016YFC1306700, 81473190, 81603090, 81761138048, 81673410, 81322048)
- National Key Research and Development Program of China (2016YFC1306700, 2016YFC1305802, 2016YFC1305800, 2017YFA0104303)
- Fundamental Research Funds for the Central Universities (2017YFA0104303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- circular RNA, major depressive disorder, depression-like behavior, miR-9, HECTD1, microglial activation, chronic unpredictable mild stress, lipopolysaccharide, peripheral blood biomarkers, therapeutic target
- MeSH terms
- RNA, Circular, Animals, Major Depressive Disorder, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Microglia, HSP90 Heat-Shock Proteins, MicroRNAs, Mice, Ubiquitination
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