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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

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

Authors :
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
Source :
Scientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
Publication Year :
2021
Publisher :
Nature Portfolio, 2021.

Abstract

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
20452322
Volume :
11
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.2b7bf52ba2a84cd397c6d506c487c83c
Document Type :
article
Full Text :
https://doi.org/10.1038/s41598-021-85656-x