REVIEW article
Front. Genet.
Sec. RNA
This article is part of the Research TopicInsights in RNA: 2025View all articles
Biogenesis and Function of Circular RNAs and Their Implications in the Down Syndrome Brain
Provisionally accepted
- 1Universiti Malaysia Terengganu Fakulti Sains dan Sekitaran Marin, Kuala Terengganu, Malaysia
- 2Universiti Putra Malaysia Jabatan Anatomi Manusia, Serdang, Malaysia
- 3Universiti Putra Malaysia Institut Penyelidikan Penuaan Malaysia, Serdang, Malaysia
- 4Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
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Circular RNAs (circRNAs), a class of covalently closed, non-coding RNAs, have recently emerged as crucial regulators of gene expression. They exert their roles through microRNA (miRNA) sponging, transcriptional regulation, and interactions with RNA-binding proteins (RBPs). Increasing evidence suggests that circRNAs play important roles in neurodevelopmental disorders, including Down syndrome (DS). DS is a condition caused by trisomy of chromosome 21 and characterised by intellectual disability (ID), neuroinflammation, and increased risk of early-onset Alzheimer's disease (AD). Aberrant circRNA expression in DS may contribute to pathogenesis by disrupting competing endogenous RNA (ceRNA) networks, modulating synaptic plasticity, and influencing key molecular pathways, including EZH2-mediated chromatin remodelling, immune response regulation, and neuronal differentiation. Despite these emerging insights, the role of circRNAs in DS remains largely underexplored compared to their well-recognised functions in cancer and other neurological disorders. Most current studies have focused on transcriptomic analyses, identifying differentially expressed circRNAs and predicting their interactions with miRNAs and mRNAs. However, these findings require further experimental validation to uncover the precise mechanisms through which circRNAs contribute to DS pathophysiology. This review highlights the association of circRNAs with DS, emphasising their dysregulation and mechanistic interactions with miRNAs and mRNAs. It further explores how these circRNA-mediated mechanisms may contribute to intellectual disability and impaired neurodevelopment, based on current evidence.
Keywords: circular RNA, Down Syndrome, miRNA sponging, cognitive development, Generegulation
Received: 18 Sep 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Zainal Abidin, Razali, Cheah and Ling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: King-Hwa Ling, lkh@upm.edu.my
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