Circular RNA-encoded protein as a novel endogenous regulator in major depressive disorder
image: Differentially expressed circFKBP8(5S,6) is a circular RNA with coding potential identified in control volunteers and patients with major depressive disorder (MDD). cFKBP8 is the protein encoded by circFKBP8(5S,6) validated by both human cell lines and monkey brains. The expression of circFKBP8(5S,6) or cFKBP8 was proven to be related to MDD using different human-derived samples, including neuronal-derived exosomes, cerebral organoids, and brain slices. Furthermore, mice experiments presented susceptibility to chronic, unpredicted mild stress (CUMS) and short CUMS after overexpressing circFKBP8(5S,6) or cFKBP8. The effects of circFKBP8(5S,6) are exerted by inhibiting GR nucleus translocation. Created using Biorender.com.
Credit: ©Science China Press
Major depressive disorder (MDD) is a debilitating mental health condition that ranks second in the global burden of human diseases. The etiology and pathogenesis of MDD remain poorly understood, which hinders the development of reliable diagnostic and therapeutic biomarkers. The study entitled “circFKBP8(5S,6)-encoded protein as a novel endogenous regulator in major depressive disorder by inhibiting glucocorticoid receptor nucleus translocation” led by Professor Zhijun Zhang’s research team from Southeast University and Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences was published in Science Bulletin. This study identified circFKBP8(5S,6) as an MDD-associated circular RNA (circRNA) with protein-encoding potential and participates in MDD pathogenesis by inhibiting glucocorticoid receptor (GR) nucleus translocation. It provides new ideas and empirical evidence for the value of circRNA-encoded proteins as diagnostic biomarkers and drug targets.
CircRNAs are covalently closed, single-stranded, regulatory RNA derived from back-splicing of pre-mRNA, which regulate gene expression by sponging miRNA or interacting with RNA binding proteins. Excitedly, recent findings suggested that circRNAs could undergo cap-independent translation to produce functional proteins implicated in the pathogenesis of human disease, especially various cancers. Regrettably, there have been no reports to date of translatable circRNAs participating in the pathogenesis of mental disorders including depression.
This study identified circFKBP8(5S,6) with protein-encoding potential from dysregulated cicRNAs in the plasma of MDD patients. It is primate-specific and composed of 391 nucleotides (nt) formed by back-splicing the truncated exon 5 and exon 6 of the FKBP8 gene. Importantly, open reading frame prediction followed by Immunoprecipitation and LC-MS/MS proved the 127-aa peptide encoded by circFKBP8(5S,6). Endogenous expression of circFKBP8(5S,6)-encoded protein was further validated in core emotion-related brain regions of cynomolgus macaques, especially for the dorsolateral prefrontal cortex (DLPFC).
circFKBP8(5S,6) is upregulated in dexamethasone-stressed SH-SY5Y human neuroblastoma cells and its overexpression led to dysregulated genes enriched with depression. circFKBP8(5S,6) or its encoding protein consistently increased in neuron-derived plasma exosomes, postmortem hypothalamus sections, and iPS cell-derived organoids from MDD patients. Overexpression of circFKBP8(5S,6) or its coding protein, but not the translation defect circFKBP8(5S,6), in the prelimbic cortex of mice increased the sensitivity of mice to chronic unpredicted mild stress (CUMS). The mechanistic study revealed circFKBP8(5S,6) or its encoding protein-suppressed nucleus translocation of GR in dexamethasone-stressed SH-SY5Y cells and depression-like mice. The findings were reversal validated in circFKBP8(5S,6)-targeted knocking-down MDD organoids.
In summary, this study combined cross-species research systems to understand the translational ability of circFKBP8(5S,6). The encoded cFKBP8 blocks GR entry into neuronal nuclei which has been recognized as related to the impairment of HPA axis function and depression. Overall, this study presents novel ideas and evidence by screening and identifying a protein-encoding circRNA in MDD and elucidating the mechanism of the translated protein. As a translatable circRNA, circFKBP8(5S,6) appears to be a reliable candidate as a diagnostic biomarker and therapeutic target.
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circFKBP8(5S,6)-encoded protein as a novel endogenous regulator in major depressive disorder by inhibiting glucocorticoid receptor nucleus translocation.