The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MS...

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Autores principales:	Kim Le Cann, Alec Foerster, Corinna Rösseler, Andelain Erickson, Petra Hautvast, Sebastian Giesselmann, Daniel Pensold, Ingo Kurth, Markus Rothermel, Virginia B. Mattis, Geraldine Zimmer-Bensch, Stephan von Hörsten, Bernd Denecke, Tim Clarner, Jannis Meents, Angelika Lampert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b7bf52ba2a84cd397c6d506c487c83c
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spelling	oai:doaj.org-article:2b7bf52ba2a84cd397c6d506c487c83c2021-12-02T13:24:26ZThe difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells10.1038/s41598-021-85656-x2045-2322https://doaj.org/article/2b7bf52ba2a84cd397c6d506c487c83c2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85656-xhttps://doaj.org/toc/2045-2322Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.Kim Le CannAlec FoersterCorinna RösselerAndelain EricksonPetra HautvastSebastian GiesselmannDaniel PensoldIngo KurthMarkus RothermelVirginia B. MattisGeraldine Zimmer-BenschStephan von HörstenBernd DeneckeTim ClarnerJannis MeentsAngelika LampertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kim Le Cann Alec Foerster Corinna Rösseler Andelain Erickson Petra Hautvast Sebastian Giesselmann Daniel Pensold Ingo Kurth Markus Rothermel Virginia B. Mattis Geraldine Zimmer-Bensch Stephan von Hörsten Bernd Denecke Tim Clarner Jannis Meents Angelika Lampert The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
description	Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.
format	article
author	Kim Le Cann Alec Foerster Corinna Rösseler Andelain Erickson Petra Hautvast Sebastian Giesselmann Daniel Pensold Ingo Kurth Markus Rothermel Virginia B. Mattis Geraldine Zimmer-Bensch Stephan von Hörsten Bernd Denecke Tim Clarner Jannis Meents Angelika Lampert
author_facet	Kim Le Cann Alec Foerster Corinna Rösseler Andelain Erickson Petra Hautvast Sebastian Giesselmann Daniel Pensold Ingo Kurth Markus Rothermel Virginia B. Mattis Geraldine Zimmer-Bensch Stephan von Hörsten Bernd Denecke Tim Clarner Jannis Meents Angelika Lampert
author_sort	Kim Le Cann
title	The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
title_short	The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
title_full	The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
title_fullStr	The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
title_full_unstemmed	The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
title_sort	difficulty to model huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2b7bf52ba2a84cd397c6d506c487c83c
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The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

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