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Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease

The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study...

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Autores principales: Sanadgol, Nima, Amini, Javad, Beyer, Cordian, Zendedel, Adib
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527059/
https://www.ncbi.nlm.nih.gov/pubmed/37759801
http://dx.doi.org/10.3390/biom13091401
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author Sanadgol, Nima
Amini, Javad
Beyer, Cordian
Zendedel, Adib
author_facet Sanadgol, Nima
Amini, Javad
Beyer, Cordian
Zendedel, Adib
author_sort Sanadgol, Nima
collection PubMed
description The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-β and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-β and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aβ42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-β, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-β. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD.
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spelling pubmed-105270592023-09-28 Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease Sanadgol, Nima Amini, Javad Beyer, Cordian Zendedel, Adib Biomolecules Article The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-β and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-β and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aβ42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-β, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-β. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD. MDPI 2023-09-17 /pmc/articles/PMC10527059/ /pubmed/37759801 http://dx.doi.org/10.3390/biom13091401 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sanadgol, Nima
Amini, Javad
Beyer, Cordian
Zendedel, Adib
Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title_full Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title_fullStr Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title_full_unstemmed Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title_short Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease
title_sort presenilin-1-derived circular rnas: neglected epigenetic regulators with various functions in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527059/
https://www.ncbi.nlm.nih.gov/pubmed/37759801
http://dx.doi.org/10.3390/biom13091401
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