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

Cell Rep. 2021 Oct 19;37(3):109864. doi: 10.1016/j.celrep.2021.109864.


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: LRRK2; NR2F1; Parkinson's disease; dopaminergic neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology*
  • Brain / pathology
  • COUP Transcription Factor I / genetics
  • COUP Transcription Factor I / metabolism*
  • Cell Cycle
  • Cell Line
  • Cell Proliferation
  • Cell Survival
  • Dopaminergic Neurons / enzymology*
  • Dopaminergic Neurons / pathology
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / enzymology*
  • Induced Pluripotent Stem Cells / pathology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Mutation
  • Neural Stem Cells / enzymology*
  • Neural Stem Cells / pathology
  • Neurogenesis*
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology
  • Phenotype
  • RNA-Seq
  • Signal Transduction
  • Single-Cell Analysis
  • Time Factors


  • COUP Transcription Factor I
  • NR2F1 protein, human
  • Nr2f1 protein, mouse
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse