title: Rpph1Upregulates CDC42 Expression and Promotes Hippocampal Neuron Dendritic Spine Formation by Competing with miR-330-5p.
abstract: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik,Rpph1, A830012C17Rik, and Gm15477) and five miRNAs (miR-182-5p, miR-330-5p, miR-326-3p, miR-132-3p, and miR-484) are enriched in nine pathways and an AD-related gene pool. Among them, Ribonuclease P RNA component H1 (Rpph1) is upregulated in the cortex of APPswe/PS1ΔE9 mice compared to wild type controls.Rpph1binds to miR326-3p/miR-330-5p and causes the release of their downstream targetCdc42, which leads to CDC42 upregulation. This effect was disrupted upon mutation of the MRE onRpph1. Moreover, overexpression ofRpph1increased dendritic spine density in primary cultured hippocampal pyramidal neurons, whereas knocking down ofRpph1had the reverse effect. In conclusion,Rpph1modulates CDC42 expression level in a ceRNA-dependent manner, which may represent a compensatory mechanism in the early stage of the AD pathogenesis.
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Ziling
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Jia
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Hongxue
authors.initials: H
authors.lastname: Luo
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Ye
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center Shenzhen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical CenterShenzhen, China; Division of Life Science, The Hong Kong University of Science and TechnologyHong Kong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
keywords: Alzheimer’s disease (AD); CDC42; competing endogenous RNA (ceRNAs); miR-330-5p; ribonuclease P RNA component H1 (Rpph1); spine formation