CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination

Yuan Zhang,Liang Gong,Honghong Yao,Zhijun Zhang,Rongrong Huang,Gang Hu,Cancan He,Chunming Xie,Longfei Du,Ying Bai,Junxu Li,Ling Gu,Bing Han,Ling Shen,Haisan Zhang,Hongxing Zhang,Pei Liu,Jie Chao

doi:10.1038/s41380-018-0285-0

Abstract

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.

Highlights

These authors contributed : Yuan Zhang, Longfei Du, Ying Bai, Bing Han, Cancan HeElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Major depressive disorder (MDD), characterized by emotional dysfunction, is one of the most prevalent psychiatric disorders worldwide and a major public health concern associated with grave consequences [1,2,3,4]
Since HSP90 is the substrate of ubiquitination mediated by homologous to the E6-AP C-terminal (HECT) domain E3 ubiquitin protein ligase 1 (HECTD1) and is involved in microglial activation, we examined the effect of LPS on HSP90 ubiquitination
Our study demonstrated that circular RNA DYM (circDYM) is downregulated in both the peripheral blood of MDD patients and the depressive-like animal models

Summary

Introduction

MDD arises from a combination of genetic and environmental factors [5]. 10 Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 Jiangsu, China with stress being a major risk factor that can lead to the precipitation of depression [6]. With a lack of clinical biomarkers, MDD is currently diagnosed by subjective symptoms. Due to the heterogeneity of depression and low recognition rate of high-risk individuals, symptom-based diagnosis is clinically inadequate and does not lead to accurate classification of depression [7, 8]. There is a lack of effective antidepressant drugs; roughly one-third of patients experience an inadequate response [9, 10]. Further understanding of the detailed mechanisms of depression is needed to identify more effective therapeutic targets

Methods

Results

Conclusion