Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies
Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients’ brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer’s disease. Recently, we described a 17q21.31 duplication in patients presen...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | Stem Cell Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506122001118 |
| _version_ | 1811307216132636672 |
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| author | Laetitia Miguel Anne Rovelet-Lecrux Pascal Chambon Géraldine Joly-Helas Stéphane Rousseau David Wallon Stéphane Epelbaum Thierry Frébourg Dominique Campion Gaël Nicolas Magalie Lecourtois |
| author_facet | Laetitia Miguel Anne Rovelet-Lecrux Pascal Chambon Géraldine Joly-Helas Stéphane Rousseau David Wallon Stéphane Epelbaum Thierry Frébourg Dominique Campion Gaël Nicolas Magalie Lecourtois |
| author_sort | Laetitia Miguel |
| collection | DOAJ |
| description | Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients’ brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer’s disease. Recently, we described a 17q21.31 duplication in patients presenting different cognitive or motor symptoms and characterized by the accumulation of different Tau isoforms. This duplication involves four genes, including the MAPT gene that encodes the Tau protein. The main pathophysiological consequence associated with this duplication was a 1.6–1.9-fold increase in the MAPT messenger RNA as measured in blood samples of duplication carriers. However, the pathophysiological consequences of this duplication in a cell type relevant for neurodegenerative diseases have never been explored so far. In this study, we developed the first model of primary tauopathy linked to a 17q21.31 duplication in iPSC-induced neurons from 2 unrelated carriers. As in patients’ blood, we demonstrated that this duplication was associated with an increase in MAPT mRNA resulting in elevated Tau protein levels in iPSC-derived cortical neurons. We believe that these iPSC lines will be a pertinent tool to elucidate how a same genetic cause could lead to distinct types of tauopathies and the pathophysiological mechanisms associated with Tau-mediated neurodegeneration in the 17q21.31 duplication context. |
| first_indexed | 2024-04-13T09:01:05Z |
| format | Article |
| id | doaj.art-6a35fe3e335e4703a9c35f61050102a0 |
| institution | Directory Open Access Journal |
| issn | 1873-5061 |
| language | English |
| last_indexed | 2024-04-13T09:01:05Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Research |
| spelling | doaj.art-6a35fe3e335e4703a9c35f61050102a02022-12-22T02:53:09ZengElsevierStem Cell Research1873-50612022-05-0161102762Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathiesLaetitia Miguel0Anne Rovelet-Lecrux1Pascal Chambon2Géraldine Joly-Helas3Stéphane Rousseau4David Wallon5Stéphane Epelbaum6Thierry Frébourg7Dominique Campion8Gaël Nicolas9Magalie Lecourtois10Normandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Neurology and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceAP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié-Salpêtrière, ICM, CNRS UMR 7225, Inserm U 1127, UPMC-P6 UMR S 1127, GH Pitié-Salpêtrière, Paris, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, FranceNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000 Rouen, France; Corresponding author.Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients’ brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer’s disease. Recently, we described a 17q21.31 duplication in patients presenting different cognitive or motor symptoms and characterized by the accumulation of different Tau isoforms. This duplication involves four genes, including the MAPT gene that encodes the Tau protein. The main pathophysiological consequence associated with this duplication was a 1.6–1.9-fold increase in the MAPT messenger RNA as measured in blood samples of duplication carriers. However, the pathophysiological consequences of this duplication in a cell type relevant for neurodegenerative diseases have never been explored so far. In this study, we developed the first model of primary tauopathy linked to a 17q21.31 duplication in iPSC-induced neurons from 2 unrelated carriers. As in patients’ blood, we demonstrated that this duplication was associated with an increase in MAPT mRNA resulting in elevated Tau protein levels in iPSC-derived cortical neurons. We believe that these iPSC lines will be a pertinent tool to elucidate how a same genetic cause could lead to distinct types of tauopathies and the pathophysiological mechanisms associated with Tau-mediated neurodegeneration in the 17q21.31 duplication context.http://www.sciencedirect.com/science/article/pii/S1873506122001118TauopathiesiPSC-induced neuronsMAPT17q21.31Tau |
| spellingShingle | Laetitia Miguel Anne Rovelet-Lecrux Pascal Chambon Géraldine Joly-Helas Stéphane Rousseau David Wallon Stéphane Epelbaum Thierry Frébourg Dominique Campion Gaël Nicolas Magalie Lecourtois Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies Stem Cell Research Tauopathies iPSC-induced neurons MAPT 17q21.31 Tau |
| title | Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies |
| title_full | Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies |
| title_fullStr | Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies |
| title_full_unstemmed | Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies |
| title_short | Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies |
| title_sort | generation of 17q21 31 duplication ipsc derived neurons as a model for primary tauopathies |
| topic | Tauopathies iPSC-induced neurons MAPT 17q21.31 Tau |
| url | http://www.sciencedirect.com/science/article/pii/S1873506122001118 |
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