Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the Huntingtin gene. Transcriptional dysregulation is one of the main cellular processes affected by mutant Huntingtin (mHtt). In this study, we investigate the alterations in miR...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/11942 |
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| author | Nóra Zsindely Gábor Nagy Fruzsina Siági Anita Farkas László Bodai |
| author_facet | Nóra Zsindely Gábor Nagy Fruzsina Siági Anita Farkas László Bodai |
| author_sort | Nóra Zsindely |
| collection | DOAJ |
| description | Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the Huntingtin gene. Transcriptional dysregulation is one of the main cellular processes affected by mutant Huntingtin (mHtt). In this study, we investigate the alterations in miRNA and mRNA expression levels in a <i>Drosophila</i> model of HD by RNA sequencing and assess the functional effects of misregulated miRNAs in vivo. We found that in head samples of HD flies, the level of 32 miRNAs changed significantly; half of these were upregulated, while the other half were downregulated. After comparing miRNA and mRNA expression data, we discovered similarities in the impacted molecular pathways. Additionally, we observed that the putative targets of almost all dysregulated miRNAs were overrepresented among the upregulated mRNAs. We tested the effects of overexpression of five misregulated miRNAs in the HD model and found that while mir-10 and mir-219 enhanced, mir-137, mir-305, and mir-1010 ameliorated mHtt-induced phenotypes. Based on our results, we propose that while altered expression of mir-10, mir-137, and mir-1010 might be part of HD pathology, the upregulation of mir-305 might serve as a compensatory mechanism as a response to mHtt-induced transcriptional dysregulation. |
| first_indexed | 2024-03-11T00:26:54Z |
| format | Article |
| id | doaj.art-eefe9bcf3f1540a98f7b72d0b8418b86 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:26:54Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-eefe9bcf3f1540a98f7b72d0b8418b862023-11-18T22:58:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124151194210.3390/ijms241511942Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease ModelNóra Zsindely0Gábor Nagy1Fruzsina Siági2Anita Farkas3László Bodai4Department of Genetics, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryDepartment of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryDepartment of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryDepartment of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryDepartment of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryHuntington’s disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the Huntingtin gene. Transcriptional dysregulation is one of the main cellular processes affected by mutant Huntingtin (mHtt). In this study, we investigate the alterations in miRNA and mRNA expression levels in a <i>Drosophila</i> model of HD by RNA sequencing and assess the functional effects of misregulated miRNAs in vivo. We found that in head samples of HD flies, the level of 32 miRNAs changed significantly; half of these were upregulated, while the other half were downregulated. After comparing miRNA and mRNA expression data, we discovered similarities in the impacted molecular pathways. Additionally, we observed that the putative targets of almost all dysregulated miRNAs were overrepresented among the upregulated mRNAs. We tested the effects of overexpression of five misregulated miRNAs in the HD model and found that while mir-10 and mir-219 enhanced, mir-137, mir-305, and mir-1010 ameliorated mHtt-induced phenotypes. Based on our results, we propose that while altered expression of mir-10, mir-137, and mir-1010 might be part of HD pathology, the upregulation of mir-305 might serve as a compensatory mechanism as a response to mHtt-induced transcriptional dysregulation.https://www.mdpi.com/1422-0067/24/15/11942Huntington’s diseaseneurodegenerationmiRNAtranscriptomicstranscription<i>Drosophila</i> |
| spellingShingle | Nóra Zsindely Gábor Nagy Fruzsina Siági Anita Farkas László Bodai Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model International Journal of Molecular Sciences Huntington’s disease neurodegeneration miRNA transcriptomics transcription <i>Drosophila</i> |
| title | Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model |
| title_full | Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model |
| title_fullStr | Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model |
| title_full_unstemmed | Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model |
| title_short | Dysregulated miRNA and mRNA Expression Affect Overlapping Pathways in a Huntington’s Disease Model |
| title_sort | dysregulated mirna and mrna expression affect overlapping pathways in a huntington s disease model |
| topic | Huntington’s disease neurodegeneration miRNA transcriptomics transcription <i>Drosophila</i> |
| url | https://www.mdpi.com/1422-0067/24/15/11942 |
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