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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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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. |
format | Online Article Text |
id | pubmed-8581055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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