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-CanoRejko Krüger, Thomas Sauter, Michèle Studer, Luis Pereira de Almeida, Karl J. Tronstad, Lasse Sinkkonen, Alexander Skupin, Jens C. Schwamborn*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number109864
JournalCell Reports
Volume37
Issue number3
DOIs
Publication statusPublished - 19 Oct 2021

Keywords

  • dopaminergic neurons
  • LRRK2
  • NR2F1
  • Parkinson's disease

Fingerprint

Dive into the research topics of 'The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1'. Together they form a unique fingerprint.

Cite this