Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/103827
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Walter, Jonas | - |
dc.contributor.author | Bolognin, Silvia | - |
dc.contributor.author | Poovathingal, Suresh K. | - |
dc.contributor.author | Magni, Stefano | - |
dc.contributor.author | Gérard, Deborah | - |
dc.contributor.author | Antony, Paul M. A. | - |
dc.contributor.author | Nickels, Sarah L. | - |
dc.contributor.author | Salamanca, Luis | - |
dc.contributor.author | Berger, Emanuel | - |
dc.contributor.author | Smits, Lisa M. | - |
dc.contributor.author | Grzyb, Kamil | - |
dc.contributor.author | Perfeito, Rita | - |
dc.contributor.author | Hoel, Fredrik | - |
dc.contributor.author | Qing, Xiaobing | - |
dc.contributor.author | Ohnmacht, Jochen | - |
dc.contributor.author | Bertacchi, Michele | - |
dc.contributor.author | Jarazo, Javier | - |
dc.contributor.author | Ignac, Tomasz | - |
dc.contributor.author | Monzel, Anna S. | - |
dc.contributor.author | Gonzalez-Cano, Laura | - |
dc.contributor.author | Krüger, Rejko | - |
dc.contributor.author | Sauter, Thomas | - |
dc.contributor.author | Studer, Michèle | - |
dc.contributor.author | Almeida, Luís Pereira de | - |
dc.contributor.author | Tronstad, Karl J. | - |
dc.contributor.author | Sinkkonen, Lasse | - |
dc.contributor.author | Skupin, Alexander | - |
dc.contributor.author | Schwamborn, Jens C. | - |
dc.date.accessioned | 2022-11-30T11:16:09Z | - |
dc.date.available | 2022-11-30T11:16:09Z | - |
dc.date.issued | 2021-10-19 | - |
dc.identifier.issn | 22111247 | pt |
dc.identifier.uri | https://hdl.handle.net/10316/103827 | - |
dc.description.abstract | 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. | pt |
dc.language.iso | eng | pt |
dc.publisher | Elsevier | pt |
dc.relation | Fonds National de la Recherche´ (FNR) (CORE, C13/BM/5791363 and Proof-of-Concept program PoC15/11180855 and PoC16/11559169 | pt |
dc.relation | EU Joint Programme - Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02 and INTER/JPND/15/11092422 | pt |
dc.relation | SysMedPD project, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 668738 | pt |
dc.relation | FNR PRIDE DTU CriTiCS, reference 10907093 | pt |
dc.relation | Jerome Lejeune Foundation (grant 199162) | pt |
dc.relation | FNR Core Jr C19/BM/13626885/IDeM | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt |
dc.subject | dopaminergic neurons | pt |
dc.subject | LRRK2 | pt |
dc.subject | NR2F1 | pt |
dc.subject | Parkinson's disease | pt |
dc.subject.mesh | Animals | pt |
dc.subject.mesh | Brain | pt |
dc.subject.mesh | COUP Transcription Factor I | pt |
dc.subject.mesh | Cell Cycle | pt |
dc.subject.mesh | Cell Line | pt |
dc.subject.mesh | Cell Proliferation | pt |
dc.subject.mesh | Cell Survival | pt |
dc.subject.mesh | Dopaminergic Neurons | pt |
dc.subject.mesh | Female | pt |
dc.subject.mesh | Humans | pt |
dc.subject.mesh | Induced Pluripotent Stem Cells | pt |
dc.subject.mesh | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | pt |
dc.subject.mesh | Male | pt |
dc.subject.mesh | Mice, 129 Strain | pt |
dc.subject.mesh | Mice, Knockout | pt |
dc.subject.mesh | Mutation | pt |
dc.subject.mesh | Neural Stem Cells | pt |
dc.subject.mesh | Parkinson Disease | pt |
dc.subject.mesh | Phenotype | pt |
dc.subject.mesh | RNA-Seq | pt |
dc.subject.mesh | Signal Transduction | pt |
dc.subject.mesh | Single-Cell Analysis | pt |
dc.subject.mesh | Time Factors | pt |
dc.subject.mesh | Neurogenesis | pt |
dc.title | The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1 | pt |
dc.type | article | - |
degois.publication.firstPage | 109864 | pt |
degois.publication.issue | 3 | pt |
degois.publication.title | Cell Reports | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1016/j.celrep.2021.109864 | pt |
degois.publication.volume | 37 | pt |
dc.date.embargo | 2021-10-19 | * |
uc.date.periodoEmbargo | 0 | pt |
item.fulltext | Com Texto completo | - |
item.grantfulltext | open | - |
item.languageiso639-1 | en | - |
item.cerifentitytype | Publications | - |
item.openairetype | article | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CIBB - Center for Innovative Biomedicine and Biotechnology | - |
crisitem.author.orcid | 0000-0002-7503-637X | - |
crisitem.author.orcid | 0000-0001-5831-3307 | - |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais FFUC- Artigos em Revistas Internacionais |
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1-s2.0-S2211124721013310-main.pdf | 6.85 MB | Adobe PDF | View/Open |
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