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

  • Transversal Translational Medicine
October 19, 2021 By:
  • Walter J
  • Bolognin S
  • Poovathingal SK
  • Magni S
  • Gerard D
  • Antony PMA
  • Nickels SL
  • Salamanca L
  • Berger E
  • Smits LM
  • Grzyb K
  • Perfeito R
  • Hoel F
  • Qing X
  • Ohnmacht J
  • Bertacchi M
  • Jarazo J
  • Ignac T
  • Monzel AS
  • Gonzalez-Cano L
  • Kruger R
  • Sauter T
  • Studer M
  • de Almeida LP
  • Tronstad KJ
  • Sinkkonen L
  • Skupin A
  • Schwamborn JC.

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.

2021 Oct. Cell Rep.37(3):109864.
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