Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context
Summary: Background: Tau is a microtubule-binding protein encoded by the MAPT gene. Tau is essential for several physiological functions and associated with pathological processes, including Alzheimer's disease (AD). Six tau isoforms are typically described in the central nervous system, but c...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423005194 |
| _version_ | 1827389265112203264 |
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| author | Daniel Ruiz-Gabarre Laura Vallés-Saiz Almudena Carnero-Espejo Isidro Ferrer Félix Hernández Ramon Garcia-Escudero Jesús Ávila Vega García-Escudero |
| author_facet | Daniel Ruiz-Gabarre Laura Vallés-Saiz Almudena Carnero-Espejo Isidro Ferrer Félix Hernández Ramon Garcia-Escudero Jesús Ávila Vega García-Escudero |
| author_sort | Daniel Ruiz-Gabarre |
| collection | DOAJ |
| description | Summary: Background: Tau is a microtubule-binding protein encoded by the MAPT gene. Tau is essential for several physiological functions and associated with pathological processes, including Alzheimer's disease (AD). Six tau isoforms are typically described in the central nervous system, but current research paints a more diverse landscape and a more nuanced balance between isoforms. Recent work has described tau isoforms generated by intron 11 and intron 12 retention. This work adds to that evidence, proving the existence of MAPT transcripts retaining intron 3. Our aim is to demonstrate the existence of mature MAPT RNA species that retain intron 3 in human brain samples and to study its correlation with Alzheimer's disease across different regions. Methods: Initial evidence of intron-3-retaining MAPT species come from in silico analysis of RNA-seq databases. We further demonstrate the existence of these mature RNA species in a human neuroepithelioma cell line and human brain samples by quantitative PCR. We also use digital droplet PCR to demonstrate the existence of RNA species that retain either intron 3, intron 12 or both introns. Findings: Intron-3-retaining species are even more prominently present that intron-12-retaining ones. We show the presence of MAPT transcripts that retain both introns 3 and 12. These intron-retaining species are diminished in brain samples of patients with Alzheimer's disease with respect to individuals without dementia. Conversely, relative abundance of intron-3- or intron-12-retaining MAPT species with respect to double-retaining species as well as their percentage of expression with respect to total MAPT are increased in patients with Alzheimer's disease, especially in hippocampal samples. Among these TIR-MAPT species, TIR3+12 double truncation allows better classification potential of Alzheimer's disease samples. Moreover, we find a significant increase in intron-3- or intron-12-retaining species and its relative abundance with respect to double-retaining MAPT species in cerebellum in contrast to frontal lateral cortex and hippocampus in individuals with no signs of dementia. Interpretation: Intron retention constitutes a potential mechanism to generate Tau isoforms whose mature RNA expression levels correlate with Alzheimer's pathology showing its potential as a biomarker associated to the disease. Funding: This research was funded by the Spanish Ministry of Science, Innovation and Universities: PGC2018-096177-B-I00 (J.A.); Spanish Ministry of Science and Innovation (MCIN): PID2020-113204GB-I00 (F.H.) and PID2021-123859OB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE (J.A.). It was also supported by CSIC through an intramural grant (201920E104) (J.A.) and the Centre for Networked Biomedical Research on Neurodegenerative Diseases (J.A.). The Centro de Biología Molecular Severo Ochoa (CBMSO) is a Severo Ochoa Center of Excellence (MICIN, award CEX2021-001154-S). |
| first_indexed | 2024-03-08T16:32:05Z |
| format | Article |
| id | doaj.art-3c206599cfbe491f8d0c10951fc2ef7c |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T16:32:05Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-3c206599cfbe491f8d0c10951fc2ef7c2024-01-06T04:39:03ZengElsevierEBioMedicine2352-39642024-02-01100104953Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in contextDaniel Ruiz-Gabarre0Laura Vallés-Saiz1Almudena Carnero-Espejo2Isidro Ferrer3Félix Hernández4Ramon Garcia-Escudero5Jesús Ávila6Vega García-Escudero7Anatomy, Histology and Neuroscience Department, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain; Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049, Madrid, Spain; Graduate Programa in Neuroscience, Universidad Autónoma de Madrid (UAM), 28029, Madrid, SpainCentro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049, Madrid, SpainAnatomy, Histology and Neuroscience Department, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain; Graduate Programa in Neuroscience, Universidad Autónoma de Madrid (UAM), 28029, Madrid, SpainNetworking Research Centre on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain; Department of Pathology and Experimental Therapeutics, University of Barcelona, 08907, Barcelona, Spain; Bellvitge University Hospital, IDIBELL (Bellvitge Biomedical Research Centre), 08908, Barcelona, Spain; Institute of Neurosciences, University of Barcelona, 08035, Barcelona, SpainCentro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049, Madrid, SpainBiomedical Oncology Unit, CIEMAT, 28040, Madrid, Spain; Research Institute Hospital 12 de Octubre (imas12), 28041, Madrid, Spain; Networking Research Centre on Cancer (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, SpainCentro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049, Madrid, Spain; Networking Research Centre on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain; Corresponding author. Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049, Madrid, Spain.Anatomy, Histology and Neuroscience Department, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain; Graduate Programa in Neuroscience, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain; Networking Research Centre on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain; Institute for Molecular Biology-IUBM (Universidad Autónoma de Madrid), 28049, Madrid, Spain; Corresponding author. Anatomy, Histology and Neuroscience Department, School of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain.Summary: Background: Tau is a microtubule-binding protein encoded by the MAPT gene. Tau is essential for several physiological functions and associated with pathological processes, including Alzheimer's disease (AD). Six tau isoforms are typically described in the central nervous system, but current research paints a more diverse landscape and a more nuanced balance between isoforms. Recent work has described tau isoforms generated by intron 11 and intron 12 retention. This work adds to that evidence, proving the existence of MAPT transcripts retaining intron 3. Our aim is to demonstrate the existence of mature MAPT RNA species that retain intron 3 in human brain samples and to study its correlation with Alzheimer's disease across different regions. Methods: Initial evidence of intron-3-retaining MAPT species come from in silico analysis of RNA-seq databases. We further demonstrate the existence of these mature RNA species in a human neuroepithelioma cell line and human brain samples by quantitative PCR. We also use digital droplet PCR to demonstrate the existence of RNA species that retain either intron 3, intron 12 or both introns. Findings: Intron-3-retaining species are even more prominently present that intron-12-retaining ones. We show the presence of MAPT transcripts that retain both introns 3 and 12. These intron-retaining species are diminished in brain samples of patients with Alzheimer's disease with respect to individuals without dementia. Conversely, relative abundance of intron-3- or intron-12-retaining MAPT species with respect to double-retaining species as well as their percentage of expression with respect to total MAPT are increased in patients with Alzheimer's disease, especially in hippocampal samples. Among these TIR-MAPT species, TIR3+12 double truncation allows better classification potential of Alzheimer's disease samples. Moreover, we find a significant increase in intron-3- or intron-12-retaining species and its relative abundance with respect to double-retaining MAPT species in cerebellum in contrast to frontal lateral cortex and hippocampus in individuals with no signs of dementia. Interpretation: Intron retention constitutes a potential mechanism to generate Tau isoforms whose mature RNA expression levels correlate with Alzheimer's pathology showing its potential as a biomarker associated to the disease. Funding: This research was funded by the Spanish Ministry of Science, Innovation and Universities: PGC2018-096177-B-I00 (J.A.); Spanish Ministry of Science and Innovation (MCIN): PID2020-113204GB-I00 (F.H.) and PID2021-123859OB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE (J.A.). It was also supported by CSIC through an intramural grant (201920E104) (J.A.) and the Centre for Networked Biomedical Research on Neurodegenerative Diseases (J.A.). The Centro de Biología Molecular Severo Ochoa (CBMSO) is a Severo Ochoa Center of Excellence (MICIN, award CEX2021-001154-S).http://www.sciencedirect.com/science/article/pii/S2352396423005194TauAlzheimer's diseaseAlternative splicingIntron retentionTau isoformsTauopathies |
| spellingShingle | Daniel Ruiz-Gabarre Laura Vallés-Saiz Almudena Carnero-Espejo Isidro Ferrer Félix Hernández Ramon Garcia-Escudero Jesús Ávila Vega García-Escudero Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context EBioMedicine Tau Alzheimer's disease Alternative splicing Intron retention Tau isoforms Tauopathies |
| title | Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context |
| title_full | Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context |
| title_fullStr | Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context |
| title_full_unstemmed | Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context |
| title_short | Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3Research in context |
| title_sort | intron retention as a productive mechanism in human mapt rna species generated by retention of intron 3research in context |
| topic | Tau Alzheimer's disease Alternative splicing Intron retention Tau isoforms Tauopathies |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423005194 |
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