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Title: | The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1 | Authors: | Walter, Jonas Bolognin, Silvia Poovathingal, Suresh K. Magni, Stefano Gérard, Deborah Antony, Paul M. A. Nickels, Sarah L. Salamanca, Luis Berger, Emanuel Smits, Lisa M. Grzyb, Kamil Perfeito, Rita Hoel, Fredrik Qing, Xiaobing Ohnmacht, Jochen Bertacchi, Michele Jarazo, Javier Ignac, Tomasz Monzel, Anna S. Gonzalez-Cano, Laura Krüger, Rejko Sauter, Thomas Studer, Michèle Almeida, Luís Pereira de Tronstad, Karl J. Sinkkonen, Lasse Skupin, Alexander Schwamborn, Jens C. |
Keywords: | dopaminergic neurons; LRRK2; NR2F1; Parkinson's disease | Issue Date: | 19-Oct-2021 | Publisher: | Elsevier | Project: | Fonds National de la Recherche´ (FNR) (CORE, C13/BM/5791363 and Proof-of-Concept program PoC15/11180855 and PoC16/11559169 EU Joint Programme - Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02 and INTER/JPND/15/11092422 SysMedPD project, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 668738 FNR PRIDE DTU CriTiCS, reference 10907093 Jerome Lejeune Foundation (grant 199162) FNR Core Jr C19/BM/13626885/IDeM |
Serial title, monograph or event: | Cell Reports | Volume: | 37 | Issue: | 3 | Abstract: | Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson's disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA sequencing, we observe that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell-cycle exit with a concomitant increase in cell death. We identify the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreases in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observe accelerated dopaminergic differentiation in vivo in NR2F1-deficient mouse embryos. This suggests a pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1. | URI: | https://hdl.handle.net/10316/103827 | ISSN: | 22111247 | DOI: | 10.1016/j.celrep.2021.109864 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais FFUC- Artigos em Revistas Internacionais |
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