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STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neuro...

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Autores principales: Vigont, Vladimir A., Grekhnev, Dmitriy A., Lebedeva, Olga S., Gusev, Konstantin O., Volovikov, Egor A., Skopin, Anton Yu., Bogomazova, Alexandra N., Shuvalova, Lilia D., Zubkova, Olga A., Khomyakova, Ekaterina A., Glushankova, Lyubov N., Klyushnikov, Sergey A., Illarioshkin, Sergey N., Lagarkova, Maria A., Kaznacheyeva, Elena V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884642/
https://www.ncbi.nlm.nih.gov/pubmed/33604336
http://dx.doi.org/10.3389/fcell.2021.625231
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author Vigont, Vladimir A.
Grekhnev, Dmitriy A.
Lebedeva, Olga S.
Gusev, Konstantin O.
Volovikov, Egor A.
Skopin, Anton Yu.
Bogomazova, Alexandra N.
Shuvalova, Lilia D.
Zubkova, Olga A.
Khomyakova, Ekaterina A.
Glushankova, Lyubov N.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Lagarkova, Maria A.
Kaznacheyeva, Elena V.
author_facet Vigont, Vladimir A.
Grekhnev, Dmitriy A.
Lebedeva, Olga S.
Gusev, Konstantin O.
Volovikov, Egor A.
Skopin, Anton Yu.
Bogomazova, Alexandra N.
Shuvalova, Lilia D.
Zubkova, Olga A.
Khomyakova, Ekaterina A.
Glushankova, Lyubov N.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Lagarkova, Maria A.
Kaznacheyeva, Elena V.
author_sort Vigont, Vladimir A.
collection PubMed
description Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development.
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spelling pubmed-78846422021-02-17 STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease Vigont, Vladimir A. Grekhnev, Dmitriy A. Lebedeva, Olga S. Gusev, Konstantin O. Volovikov, Egor A. Skopin, Anton Yu. Bogomazova, Alexandra N. Shuvalova, Lilia D. Zubkova, Olga A. Khomyakova, Ekaterina A. Glushankova, Lyubov N. Klyushnikov, Sergey A. Illarioshkin, Sergey N. Lagarkova, Maria A. Kaznacheyeva, Elena V. Front Cell Dev Biol Cell and Developmental Biology Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development. Frontiers Media S.A. 2021-02-02 /pmc/articles/PMC7884642/ /pubmed/33604336 http://dx.doi.org/10.3389/fcell.2021.625231 Text en Copyright © 2021 Vigont, Grekhnev, Lebedeva, Gusev, Volovikov, Skopin, Bogomazova, Shuvalova, Zubkova, Khomyakova, Glushankova, Klyushnikov, Illarioshkin, Lagarkova and Kaznacheyeva. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Vigont, Vladimir A.
Grekhnev, Dmitriy A.
Lebedeva, Olga S.
Gusev, Konstantin O.
Volovikov, Egor A.
Skopin, Anton Yu.
Bogomazova, Alexandra N.
Shuvalova, Lilia D.
Zubkova, Olga A.
Khomyakova, Ekaterina A.
Glushankova, Lyubov N.
Klyushnikov, Sergey A.
Illarioshkin, Sergey N.
Lagarkova, Maria A.
Kaznacheyeva, Elena V.
STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title_full STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title_fullStr STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title_full_unstemmed STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title_short STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease
title_sort stim2 mediates excessive store-operated calcium entry in patient-specific ipsc-derived neurons modeling a juvenile form of huntington's disease
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884642/
https://www.ncbi.nlm.nih.gov/pubmed/33604336
http://dx.doi.org/10.3389/fcell.2021.625231
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