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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Research article

Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons

Authors: Evgeny D. Nekrasov, Vladimir A. Vigont, Sergey A. Klyushnikov, Olga S. Lebedeva, Ekaterina M. Vassina, Alexandra N. Bogomazova, Ilya V. Chestkov, Tatiana A. Semashko, Elena Kiseleva, Lyubov A. Suldina, Pavel A. Bobrovsky, Olga A. Zimina, Maria A. Ryazantseva, Anton Yu. Skopin, Sergey N. Illarioshkin, Elena V. Kaznacheyeva, Maria A. Lagarkova, Sergey L. Kiselev

Published in: Molecular Neurodegeneration | Issue 1/2016

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Abstract

Background

Huntington’s disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms.

Results

Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging.

Conclusions

Our data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug.
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Metadata
Title
Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons
Authors
Evgeny D. Nekrasov
Vladimir A. Vigont
Sergey A. Klyushnikov
Olga S. Lebedeva
Ekaterina M. Vassina
Alexandra N. Bogomazova
Ilya V. Chestkov
Tatiana A. Semashko
Elena Kiseleva
Lyubov A. Suldina
Pavel A. Bobrovsky
Olga A. Zimina
Maria A. Ryazantseva
Anton Yu. Skopin
Sergey N. Illarioshkin
Elena V. Kaznacheyeva
Maria A. Lagarkova
Sergey L. Kiselev
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0092-5

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