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

• Autor(a) principal: Walter, Jonas
• Data de Publicação: 2021
• Outros Autores: 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.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/103827; https://doi.org/10.1016/j.celrep.2021.109864
• topic: 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

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.