Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies

Laetitia Miguel (1) , Anne Rovelet-Lecrux (1) , Pascal Chambon (1) , Géraldine Joly-Helas (1) , Stéphane Rousseau (1) , David Wallon (1) , Stéphane Epelbaum (2, 3) , Thierry Frébourg (1) , Dominique Campion (1) , Gaël Nicolas (1) , Magalie Lecourtois (1)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 IM2A - Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre]
3 ICM - Institut du Cerveau = Paris Brain Institute

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.

Keywords: Tauopathies; iPSC-induced neurons; MAPT; 17q21.31; Tau

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Neurobiology

Laetitia Miguel, Anne Rovelet-Lecrux, Pascal Chambon, Géraldine Joly-Helas, Stéphane Rousseau, et al.. Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies. Stem Cell Research, 2022, 61, pp.102762. ⟨10.1016/j.scr.2022.102762⟩. ⟨hal-03622429⟩