학술논문
The Parkinson’s-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1
Document Type
article
Author
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-Cano; Rejko Krüger; Thomas Sauter; Michèle Studer; Luis Pereira de Almeida; Karl J. Tronstad; Lasse Sinkkonen; Alexander Skupin; Jens C. Schwamborn
Source
Cell Reports, Vol 37, Iss 3, Pp 109864- (2021)
Subject
Language
English
ISSN
2211-1247
Abstract
Summary: 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.