@article{97dbd62628fc497980a99a72f5cc6c82,
title = "The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1",
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.",
keywords = "dopaminergic neurons, LRRK2, NR2F1, Parkinson's disease",
author = "Jonas Walter and Silvia Bolognin and Poovathingal, {Suresh K.} and Stefano Magni and Deborah G{\'e}rard and Antony, {Paul M.A.} and Nickels, {Sarah L.} and Luis Salamanca and Emanuel Berger and Smits, {Lisa M.} and Kamil Grzyb and Rita Perfeito and Fredrik Hoel and Xiaobing Qing and Jochen Ohnmacht and Michele Bertacchi and Javier Jarazo and Tomasz Ignac and Monzel, {Anna S.} and Laura Gonzalez-Cano and Rejko Kr{\"u}ger and Thomas Sauter and Mich{\`e}le Studer and {de Almeida}, {Luis Pereira} and Tronstad, {Karl J.} and Lasse Sinkkonen and Alexander Skupin and Schwamborn, {Jens C.}",
note = "Funding Information: This project was supported by the Luxembourg Centre for Systems Biomedicine (LCSB) pluripotent stem cell core facility. The J.C.S. lab is supported by the Fonds National de la Recherch{\'e} (FNR) (CORE, C13/BM/5791363 and Proof-of-Concept program PoC15/11180855 and PoC16/11559169 ). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project ( INTER/JPND/14/02 and INTER/JPND/15/11092422 ). Further support comes from the SysMedPD project, which has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 668738 . J.W., D.G., X.Q., L.G.C., J.J., and A.M. were supported by fellowships from the FNR (AFR, Aides {\`a} la Formation-Recherch{\'e}). S.M. is supported by the FNR PRIDE DTU CriTiCS, reference 10907093 . M.B. and M.S. were supported by the Jerome Lejeune Foundation (grant 199162 ). S.B. is supported by the FNR Core Jr C19/BM/13626885/IDeM . Finally, we also thank the private donors who support our work at the Luxembourg Centre for Systems Biomedicine. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript (AAM) version arising from this submission. Funding Information: The authors would like to thank Thea van Wuellen, Marie Fossepre, Antoine Treff, and Annegraet Daujeumont for technical assistance. We thank Prof. Dr. Hans R. Sch?ler of the Max-Planck-Gesellschaft, Dr. Jared Sterneckert of the CRTD, Prof. Dr. Thomas Gasser of the Hertie Institute in Tuebingen, and the Coriell Institute for providing the cell lines and EMBL Gene Core at Heidelberg for support with high-throughput sequencing. The experiments presented in this paper were carried out using the HPC facilities of the University of Luxembourg. We also thank Prof. Dr. Ernest Arenas and Gioele La Manno for their help with Figure 1B and feedback on the manuscript. This project was supported by the Luxembourg Centre for Systems Biomedicine (LCSB) pluripotent stem cell core facility. The J.C.S. lab is supported by the Fonds National de la Recherch? (FNR) (CORE, C13/BM/5791363 and Proof-of-Concept program PoC15/11180855 and PoC16/11559169). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02 and INTER/JPND/15/11092422). Further support comes from the SysMedPD project, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 668738. J.W. D.G. X.Q. L.G.C. J.J. and A.M. were supported by fellowships from the FNR (AFR, Aides ? la Formation-Recherch?). S.M. is supported by the FNR PRIDE DTU CriTiCS, reference 10907093. M.B. and M.S. were supported by the Jerome Lejeune Foundation (grant 199162). S.B. is supported by the FNR Core Jr C19/BM/13626885/IDeM. Finally, we also thank the private donors who support our work at the Luxembourg Centre for Systems Biomedicine. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript (AAM) version arising from this submission. Conceptualization, J.W. and J.C.S.; cell culture and assay design, J.W.; methodology, J.W. S.B. P.M.A.A. S.L.N. S.K.P. L. Salamanca, S.M. R.P. F.H. X.Q. J.O. J.J. T.I. A.S.M. L.G.-C. A.S. D.G. T.S. L.M.S. K.G. M.B. E.B. K.J.T. and L. Sinkkonen; investigation, J.W. S.B. P.M.A.A. S.N. S.K.P. L. Salamanca, S.M. R.P. F.H. A.S. M.B. and K.J.T.; writing ? original draft, J.W. J.C.S. and S.B.; writing ? review & editing, all co-authors; supervision, L.P.D.A. L. Sinkkonen, A.S. M.S. K.J.T. L.P.d.A. R.K. and J.C.S. 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. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = oct,
day = "19",
doi = "10.1016/j.celrep.2021.109864",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}