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---
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title: The Parkinson’s disease associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1
permalink: /frozen/y9k6-xa72
---

{% rtitle 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 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

{% endrtitle %}

{% rblock 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. 

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{% rblock  Raw data | fas fa-video %}
The complete Dataset is available [here](https://webdav-r3lab.uni.lu/public/data/y9k6-xa72/). It is subdivided into originals (raw data) and partials (analysis) specific to each figure and supplementary present in the manuscript. 
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{% rblock  Sequencing data | fas fa-video %}
The complete RNA-seq dataset is available [here](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE128040). 
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{% rblock  Scripts | fas fa-video %}
The scripts used to analyse the data are available [here](https://github.com/LCSB-DVB/Walter_2021). 
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