Cell Reports (Oct 2021)
The Parkinson’s-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1
- 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
- Jonas Walter
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Silvia Bolognin
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Suresh K. Poovathingal
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Stefano Magni
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Deborah Gérard
- Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg
- Paul M.A. Antony
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Sarah L. Nickels
- 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
- Luis Salamanca
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Emanuel Berger
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Lisa M. Smits
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Kamil Grzyb
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Rita Perfeito
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal
- Fredrik Hoel
- Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway
- Xiaobing Qing
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Jochen Ohnmacht
- 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
- Michele Bertacchi
- Université Côte d’Azur, CNRS, Inserm, 06108 Nice, France
- Javier Jarazo
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Tomasz Ignac
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Anna S. Monzel
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Laura Gonzalez-Cano
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg
- Rejko Krüger
- 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
- Thomas Sauter
- Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg
- Michèle Studer
- Université Côte d’Azur, CNRS, Inserm, 06108 Nice, France
- Luis Pereira de Almeida
- 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
- Karl J. Tronstad
- Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway
- Lasse Sinkkonen
- Department of Life Science and Medicine (DLSM), University of Luxembourg, 4362 Belvaux, Luxembourg
- Alexander Skupin
- 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
- Jens C. Schwamborn
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Belvaux, Luxembourg; Corresponding author
- Journal volume & issue
-
Vol. 37,
no. 3
p. 109864
Abstract
Summary: 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.
