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

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dc.contributor.author Nekrasov E.
dc.contributor.author Vigont V.
dc.contributor.author Klyushnikov S.
dc.contributor.author Lebedeva O.
dc.contributor.author Vassina E.
dc.contributor.author Bogomazova A.
dc.contributor.author Chestkov I.
dc.contributor.author Semashko T.
dc.contributor.author Kiseleva E.
dc.contributor.author Suldina L.
dc.contributor.author Bobrovsky P.
dc.contributor.author Zimina O.
dc.contributor.author Ryazantseva M.
dc.contributor.author Skopin A.
dc.contributor.author Illarioshkin S.
dc.contributor.author Kaznacheyeva E.
dc.contributor.author Lagarkova M.
dc.contributor.author Kiselev S.
dc.date.accessioned 2018-09-19T22:22:27Z
dc.date.available 2018-09-19T22:22:27Z
dc.date.issued 2016
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/145121
dc.description.abstract © 2016 Nekrasov et al.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.
dc.subject Aging
dc.subject Differentiation
dc.subject GABAergic medium spiny neurons
dc.subject Human induced pluripotent stem cells
dc.subject Huntington's disease
dc.subject Neurodegeneration
dc.subject Neuroprotection
dc.subject Nuclear indentations
dc.subject Store-operated calcium entry
dc.title Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons
dc.type Article
dc.relation.ispartofseries-issue 1
dc.relation.ispartofseries-volume 11
dc.collection Публикации сотрудников КФУ
dc.source.id SCOPUS-2016-11-1-SID84963804639


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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