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

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.

MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior

“…MiR-124 and −132 are mostly restricted to the nervous system and are key to brain development through their roles in neuronal differentiation (miR-124) [61] and morphogenesis (miR-132) [62]. MiR-9 regulates microglia function through its target HECT domain E3 ubiquitin protein ligase 1 (HECTD1) [63] and miR-29a has been implicated in apoptotic pathways following endoplasmic reticulum stress via its target, an apoptosis regulator: myeloid leukemia cell differentiation protein (Mcl-1) [64]. In addition, RE1 silencing transcription factor (REST), a transcription factor involved in neuronal differentiation, was upregulated after maternal separation [52].…”

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

“…Moreover, recent studies utilized novel circRNA annotation approaches to extract circRNA expression data from RNAsequencing experiments in the dorsolateral prefrontal cortex (DLPFC) of subjects with SCZ [27,28]. Furthermore, another study uncovered alterations in a circRNA altered in the blood of patients with monopolar depression that could regulate microglial activation and depressive-like behavior in mice, thus highlighting the role of circRNAs in glial function [29]. However, nothing is known thus far about the importance of neuronal-enriched circRNAs with direct relevance to SCZ and BD in neuronal gene expression and disease-related cognition.…”

N6-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1–Regulated Astrocyte Dysfunction and Depressive-like Behaviors

“…Most circRNAs are composed of exon sequences of protein-coding genes and are highly conserved in different species, although some are also derived from intronic, intergenic, and untranslated regions. Recent studies showed that circRNAs expressing in the cytoplasm of mammal cells could act as microRNA (miRNA) sponges to block the effect of miRNA on target messenger RNA (mRNA) and regulate disease processes such as depression, stroke, and cancer (14)(15)(16). Our previous studies showed that circDYM ameliorates depressive-like behaviors by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination (15) using high-throughput sequencing and found that circRNA-mm9_circ_0015149, known as circSTAG1, was downregulated in chronic unpredictable stress (CUS)-treated mice (GEO accession number: GSE135343).…”