Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity
Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is...
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MDPI AG
2021-05-01
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| Online Access: | https://www.mdpi.com/1422-0067/22/10/5370 |
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| author | Laia Lidón Laura Llaó-Hierro Mario Nuvolone Adriano Aguzzi Jesús Ávila Isidro Ferrer José Antonio del Río Rosalina Gavín |
| author_facet | Laia Lidón Laura Llaó-Hierro Mario Nuvolone Adriano Aguzzi Jesús Ávila Isidro Ferrer José Antonio del Río Rosalina Gavín |
| author_sort | Laia Lidón |
| collection | DOAJ |
| description | Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrP<sup>C</sup>), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP<sup>C</sup> and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP<sup>C</sup> and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP<sup>C</sup> ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP<sup>C</sup> expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP<sup>C</sup> levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP<sup>C</sup> in this phenomenon. Our results indicate that PrP<sup>C</sup> plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β. |
| first_indexed | 2024-03-10T11:14:37Z |
| format | Article |
| id | doaj.art-d5a3ec2003b44bf8891b139987ed15b0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:14:37Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d5a3ec2003b44bf8891b139987ed15b02023-11-21T20:31:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210537010.3390/ijms22105370Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β ActivityLaia Lidón0Laura Llaó-Hierro1Mario Nuvolone2Adriano Aguzzi3Jesús Ávila4Isidro Ferrer5José Antonio del Río6Rosalina Gavín7Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, SpainMolecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, SpainAmyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, 27100 Pavia, ItalyInstitute of Neuropathology, University Hospital of Zurich, 8091 Zurich, SwitzerlandNetwork Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Ministry of Economy and Competitiveness, 28031 Madrid, SpainNetwork Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Ministry of Economy and Competitiveness, 28031 Madrid, SpainMolecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, SpainMolecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, SpainTau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrP<sup>C</sup>), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP<sup>C</sup> and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP<sup>C</sup> and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP<sup>C</sup> ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP<sup>C</sup> expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP<sup>C</sup> levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP<sup>C</sup> in this phenomenon. Our results indicate that PrP<sup>C</sup> plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.https://www.mdpi.com/1422-0067/22/10/5370cellular prion proteinGSK3βmicrotubule-associated protein taualternative splicingAlzheimer’s diseasetauopathies |
| spellingShingle | Laia Lidón Laura Llaó-Hierro Mario Nuvolone Adriano Aguzzi Jesús Ávila Isidro Ferrer José Antonio del Río Rosalina Gavín Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity International Journal of Molecular Sciences cellular prion protein GSK3β microtubule-associated protein tau alternative splicing Alzheimer’s disease tauopathies |
| title | Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity |
| title_full | Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity |
| title_fullStr | Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity |
| title_full_unstemmed | Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity |
| title_short | Tau Exon 10 Inclusion by PrP<sup>C</sup> through Downregulating GSK3β Activity |
| title_sort | tau exon 10 inclusion by prp sup c sup through downregulating gsk3β activity |
| topic | cellular prion protein GSK3β microtubule-associated protein tau alternative splicing Alzheimer’s disease tauopathies |
| url | https://www.mdpi.com/1422-0067/22/10/5370 |
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