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Walter J, Bolognin S, Poovathingal SK, et al. The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1. Cell Rep. 2021;37(3):109864doi: 10.1016/j.celrep.2021.109864.
Walter, J., Bolognin, S., Poovathingal, S. K., Magni, S., Gérard, D., Antony, P. M. A., Nickels, S. L., Salamanca, L., Berger, E., Smits, L. M., Grzyb, K., Perfeito, R., Hoel, F., Qing, X., Ohnmacht, J., Bertacchi, M., Jarazo, J., Ignac, T., Monzel, A. S., Gonzalez-Cano, L., Krüger, R., Sauter, T., Studer, M., de Almeida, L. P., Tronstad, K. J., Sinkkonen, L., Skupin, A., & Schwamborn, J. C. (2021). The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1. Cell reports, 37(3), 109864. https://doi.org/10.1016/j.celrep.2021.109864
Walter, Jonas, et al. "The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1." Cell reports vol. 37,3 (2021): 109864. doi: https://doi.org/10.1016/j.celrep.2021.109864
Walter J, Bolognin S, Poovathingal SK, Magni S, Gérard D, Antony PMA, Nickels SL, Salamanca L, Berger E, Smits LM, Grzyb K, Perfeito R, Hoel F, Qing X, Ohnmacht J, Bertacchi M, Jarazo J, Ignac T, Monzel AS, Gonzalez-Cano L, Krüger R, Sauter T, Studer M, de Almeida LP, Tronstad KJ, Sinkkonen L, Skupin A, Schwamborn JC. The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1. Cell Rep. 2021 Oct 19;37(3):109864. doi: 10.1016/j.celrep.2021.109864. PMID: 34686322.
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Cell Rep. 2021 Oct 19;37(3):109864. doi: 10.1016/j.celrep.2021.109864.

The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1.

Cell reports

Jonas Walter, Silvia Bolognin, Suresh K Poovathingal, Stefano Magni, Deborah Gérard, Paul M A Antony, Sarah L Nickels, Luis Salamanca, Emanuel Berger, Lisa M Smits, Kamil Grzyb, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Jochen Ohnmacht, Michele Bertacchi, Javier Jarazo, Tomasz Ignac, Anna S Monzel, Laura Gonzalez-Cano, Rejko Krüger, Thomas Sauter, Michèle Studer, Luis Pereira de Almeida, Karl J Tronstad, Lasse Sinkkonen, Alexander Skupin, Jens C Schwamborn

Affiliations

  1. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg.
  2. Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg.
  3. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg; Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg.
  4. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.
  5. Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway.
  6. Université Côte d'Azur, CNRS, Inserm, 06108 Nice, France.
  7. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
  8. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
  9. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg; Center for Research of Biological Systems, University of California, San Diego, La Jolla, CA 92093, USA.
  10. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg. Electronic address: [email protected].

PMID: 34686322 DOI: 10.1016/j.celrep.2021.109864

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: LRRK2; NR2F1; Parkinson's disease; dopaminergic neurons

Conflict of interest statement

Declaration of interests J.C.S., J.J., and S.B. are shareholders of the spin-off company OrganoTherapeutics sarl. J.C.S. and J.J. are also partially paid by the company.

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