The Difficulty to Model Huntington's Disease in Vitro Using Striatal Medium Spiny Neurons Differentiated from Human Induced Pluripotent Stem Cells

Overview

Journal Sci Rep

Specialty Science

Date 2021 Mar 26

PMID 33767215

Citations 13

Authors

Kim Le Cann

Alec Foerster

Corinna Rosseler

Andelain Erickson

Petra Hautvast

Sebastian Giesselmann

Daniel Pensold

Ingo Kurth

Markus Rothermel

Virginia B Mattis

Geraldine Zimmer-Bensch

Stephan von Horsten

Bernd Denecke

Tim Clarner

Jannis Meents

Angelika Lampert

Affiliations

Soon will be listed here.

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.

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