Down syndrome (DS) is the most example of aneuploidy, resulting from an additional copy of all or part of chromosome 21. Competing endogenous RNAs (ceRNAs) play important roles in neuronal development and neurological defects. This study aimed to identify hub genes and synergistic crosstalk among ceRNAs in the DS fetal hippocampus as potential targets for the treatment of DS-related neurodegenerative diseases. We profiled differentially expressed long non-coding RNAs (DElncRNAs), differentially expressed circular RNAs (DEcircRNAs), differentially expressed microRNAs (DEmiRNAs), and differentially expressed messenger RNAs (DEmRNAs) in hippocampal samples from patients with or without DS. Functional enrichment analysis and gene set enrichment analysis were performed, and chromosome 21-related ceRNA and protein–protein interaction networks were constructed. Additionally, the correlations between lncRNA-mRNA and miRNA-mRNA expression in the samples and HEK293T cells were validated. Our finding of changes in the expression of some key genes and ncRNAs on chromosome 21 in DS might not fully conform to the gene dosage hypothesis. Moreover, we found that four lncRNAs (MIR99AHG, PLCB4, SNHG14, GIGYF2) and one circRNA (hsa_circ_0061697) may competitively bind with three miRNAs (hsa-miR-548b-5p, miR-730-5p, and hsa-miR-548i) and subsequently regulate five mRNAs (beta-1,3-galactosyltransferase 5 [B3GALT5], helicase lymphoid-specific [HELLS], thrombospondin-2 [THBS2], glycinamide ribonucleotide transformylase [GART], clathrin heavy chain like 1 [CLTCL1]). These RNAs, whether located on chromosome 21 or not, interact with each other and might activate the PI3K/Akt/mTOR and Wnt signaling pathways, which are involved in autophagosome formation and tau hyperphosphorylation, possibly leading to adverse consequences of trisomy 21. These findings provide researchers with a better understanding of the fundamental molecular mechanisms underlying DS-related progressive defects in neuronal development.

唐氏综合症 (DS) 是非整倍体的最典型例子，由 21 号染色体全部或部分的额外副本引起。竞争性内源 RNA (ceRNA) 在神经元发育和神经缺陷中发挥着重要作用。本研究旨在确定 DS 胎儿海马中的中枢基因和 ceRNA 之间的协同串扰，作为治疗 DS 相关神经退行性疾病的潜在靶标。我们对患有或不患有 DS 患者的海马样本中差异表达的长非编码 RNA (DElncRNA)、差异表达的环状 RNA (DEcircRNA)、差异表达的 microRNA (DEmiRNA) 和差异表达的信使 RNA (DEmRNA) 进行了分析。进行功能富集分析和基因集富集分析，构建21号染色体相关的ceRNA和蛋白质-蛋白质相互作用网络。此外，还验证了样本和 HEK293T 细胞中 lncRNA-mRNA 和 miRNA-mRNA 表达之间的相关性。我们发现 DS 21 号染色体上一些关键基因和 ncRNA 表达的变化可能并不完全符合基因剂量假设。此外，我们发现四种lncRNA（MIR99AHG，PLCB4，SNHG14，GIGYF2）和一种circRNA（hsa_circ_0061697 ）可能与三种miRNA（ hsa-miR-548b-5p，miR-730-5p和hsa-miR-548i）竞争性结合。随后调节 5 个 mRNA（β-1,3-半乳糖基转移酶 5 [ B3GALT5 ]、淋巴特异性解旋酶[ HELLS ]、血小板反应蛋白-2 [ THBS2 ]、甘氨酰胺核糖核苷酸转化酶[ GART ]、网格蛋白重链样 1 [ CLTCL1 ]）。这些 RNA，无论是否位于 21 号染色体上，都会相互作用，并可能激活 PI3K/Akt/mTOR 和 Wnt 信号通路，这些信号通路参与自噬体形成和 tau 过度磷酸化，可能导致 21 三体性的不良后果。使研究人员能够更好地了解神经元发育中 DS 相关进行性缺陷的基本分子机制。