The Parkinson’s disease associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1#

Authors#

Jonas Walter, Silvia Bolognin, Suresh K Poovathingal, Stefano Magni, Deborah Gérard, Paul MA 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

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.