Autor(es):
Walter, Jonas ; Bolognin, Silvia ; Poovathingal, Suresh K. ; Magni, Stefano ; Gérard, Deborah ; Antony, Paul M. A. ; Nickels, Sarah L. ; Salamanca, Luis ; Berger, Emanuel ; Smits, Lisa M. ; Grzyb, Kamil ; Perfeito, Rita ; Hoel, Fredrik ; Qing, Xiaobing ; Ohnmacht, Jochen ; Bertacchi, Michele ; Jarazo, Javier ; Ignac, Tomasz ; Monzel, Anna S. ; Gonzalez-Cano, Laura ; Krüger, Rejko ; Sauter, Thomas ; Studer, Michèle ; Almeida, Luís Pereira de ; Tronstad, Karl J. ; Sinkkonen, Lasse ; Skupin, Alexander ; Schwamborn, Jens C.
Data: 2021
Identificador Persistente: https://hdl.handle.net/10316/103827
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): dopaminergic neurons; LRRK2; NR2F1; Parkinson's disease; Animals; Brain; COUP Transcription Factor I; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Dopaminergic Neurons; Female; Humans; Induced Pluripotent Stem Cells; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice, 129 Strain; Mice, Knockout; Mutation; Neural Stem Cells; Parkinson Disease; Phenotype; RNA-Seq; Signal Transduction; Single-Cell Analysis; Time Factors; Neurogenesis
Descrição
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.
