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Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease

In Parkinson’s disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or...

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Autores principales: Oosterveen, Tony, Garção, Pedro, Moles-Garcia, Emma, Soleilhavoup, Clement, Travaglio, Marco, Sheraz, Shahida, Peltrini, Rosa, Patrick, Kieran, Labas, Valerie, Combes-Soia, Lucie, Marklund, Ulrika, Hohenstein, Peter, Panman, Lia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581055/
https://www.ncbi.nlm.nih.gov/pubmed/34678205
http://dx.doi.org/10.1016/j.stemcr.2021.09.014
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author Oosterveen, Tony
Garção, Pedro
Moles-Garcia, Emma
Soleilhavoup, Clement
Travaglio, Marco
Sheraz, Shahida
Peltrini, Rosa
Patrick, Kieran
Labas, Valerie
Combes-Soia, Lucie
Marklund, Ulrika
Hohenstein, Peter
Panman, Lia
author_facet Oosterveen, Tony
Garção, Pedro
Moles-Garcia, Emma
Soleilhavoup, Clement
Travaglio, Marco
Sheraz, Shahida
Peltrini, Rosa
Patrick, Kieran
Labas, Valerie
Combes-Soia, Lucie
Marklund, Ulrika
Hohenstein, Peter
Panman, Lia
author_sort Oosterveen, Tony
collection PubMed
description In Parkinson’s disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN- and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN- or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery.
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spelling pubmed-85810552021-11-18 Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease Oosterveen, Tony Garção, Pedro Moles-Garcia, Emma Soleilhavoup, Clement Travaglio, Marco Sheraz, Shahida Peltrini, Rosa Patrick, Kieran Labas, Valerie Combes-Soia, Lucie Marklund, Ulrika Hohenstein, Peter Panman, Lia Stem Cell Reports Article In Parkinson’s disease (PD), substantia nigra (SN) dopaminergic (DA) neurons degenerate, while related ventral tegmental area (VTA) DA neurons remain relatively unaffected. Here, we present a methodology that directs the differentiation of mouse and human pluripotent stem cells toward either SN- or VTA-like DA lineage and models their distinct vulnerabilities. We show that the level of WNT activity is critical for the induction of the SN- and VTA-lineage transcription factors Sox6 and Otx2, respectively. Both WNT signaling modulation and forced expression of these transcription factors can drive DA neurons toward the SN- or VTA-like fate. Importantly, the SN-like lineage enriched DA cultures recapitulate the selective sensitivity to mitochondrial toxins as observed in PD, while VTA-like neuron-enriched cultures are more resistant. Furthermore, a proteomics approach led to the identification of compounds that alter SN neuronal survival, demonstrating the utility of our strategy for disease modeling and drug discovery. Elsevier 2021-10-21 /pmc/articles/PMC8581055/ /pubmed/34678205 http://dx.doi.org/10.1016/j.stemcr.2021.09.014 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Oosterveen, Tony
Garção, Pedro
Moles-Garcia, Emma
Soleilhavoup, Clement
Travaglio, Marco
Sheraz, Shahida
Peltrini, Rosa
Patrick, Kieran
Labas, Valerie
Combes-Soia, Lucie
Marklund, Ulrika
Hohenstein, Peter
Panman, Lia
Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title_full Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title_fullStr Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title_full_unstemmed Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title_short Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson’s disease
title_sort pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581055/
https://www.ncbi.nlm.nih.gov/pubmed/34678205
http://dx.doi.org/10.1016/j.stemcr.2021.09.014
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