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

• Published in: Molecular psychiatry Vol. 25; no. 6; pp. 1175 - 1190
• Main Authors: Zhang, Yuan, Du, Longfei, Bai, Ying, Han, Bing, He, Cancan, Gong, Liang, Huang, Rongrong, Shen, Ling, Chao, Jie, Liu, Pei, Zhang, Hongxing, Zhang, Haisan, Gu, Ling, Li, Junxu, Hu, Gang, Xie, Chunming, Zhang, Zhijun, Yao, Honghong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/21; 13/51; 14/19; 14/32; 38; 38/77; 38/90; 631/337; 631/378; 64/60; Alzheimer's disease; Analysis; Animal models; Animals; Behavioral Sciences; Biological Psychology; Central nervous system; Circular RNA; Depression, Mental; Depressive Disorder, Major - genetics; Disease Models, Animal; Heat shock proteins; Hospitals; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Laboratories; Lipopolysaccharides; Male; Medicine; Medicine & Public Health; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; Microglia - metabolism; MicroRNAs; MicroRNAs - genetics; miRNA; Mitogens; Neurosciences; Pathogenesis; Pathophysiology; Peripheral blood; Pharmacology; Pharmacotherapy; Psychiatry; Public health; RNA; RNA, Circular - genetics; Therapeutic applications; Type 2 diabetes; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Ubiquitination - genetics; Zhang Yuan; China
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-018-0285-0

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.