Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting
Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lac...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.00696/full |
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| author | Vladimir Vigont Evgeny Nekrasov Alexey Shalygin Konstantin Gusev Sergey Klushnikov Sergey Illarioshkin Maria Lagarkova Maria Lagarkova Sergey L. Kiselev Elena Kaznacheyeva |
| author_facet | Vladimir Vigont Evgeny Nekrasov Alexey Shalygin Konstantin Gusev Sergey Klushnikov Sergey Illarioshkin Maria Lagarkova Maria Lagarkova Sergey L. Kiselev Elena Kaznacheyeva |
| author_sort | Vladimir Vigont |
| collection | DOAJ |
| description | Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington’s disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, ICRAC and ISOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either ICRAC or ISOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both ICRAC and ISOC. |
| first_indexed | 2024-12-23T11:16:04Z |
| format | Article |
| id | doaj.art-37561a70256a4dc488738b4fe63e6e30 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-23T11:16:04Z |
| publishDate | 2018-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-37561a70256a4dc488738b4fe63e6e302022-12-21T17:49:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-06-01910.3389/fphar.2018.00696384042Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug TargetingVladimir Vigont0Evgeny Nekrasov1Alexey Shalygin2Konstantin Gusev3Sergey Klushnikov4Sergey Illarioshkin5Maria Lagarkova6Maria Lagarkova7Sergey L. Kiselev8Elena Kaznacheyeva9Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, RussiaVavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, RussiaInstitute of Cytology, Russian Academy of Sciences, Saint Petersburg, RussiaInstitute of Cytology, Russian Academy of Sciences, Saint Petersburg, RussiaScientific Center of Neurology, Russian Academy of Medical Sciences, Moscow, RussiaScientific Center of Neurology, Russian Academy of Medical Sciences, Moscow, RussiaVavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, RussiaFederal Research and Clinical Center of Physical-Chemical Medicine, Moscow, RussiaVavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, RussiaInstitute of Cytology, Russian Academy of Sciences, Saint Petersburg, RussiaNeurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington’s disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, ICRAC and ISOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either ICRAC or ISOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both ICRAC and ISOC.https://www.frontiersin.org/article/10.3389/fphar.2018.00696/fullstore-operated calcium channelsSOCHuntington’s diseaseneurodegenerationEVP4593iPS cells |
| spellingShingle | Vladimir Vigont Evgeny Nekrasov Alexey Shalygin Konstantin Gusev Sergey Klushnikov Sergey Illarioshkin Maria Lagarkova Maria Lagarkova Sergey L. Kiselev Elena Kaznacheyeva Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting Frontiers in Pharmacology store-operated calcium channels SOC Huntington’s disease neurodegeneration EVP4593 iPS cells |
| title | Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting |
| title_full | Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting |
| title_fullStr | Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting |
| title_full_unstemmed | Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting |
| title_short | Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting |
| title_sort | patient specific ipsc based models of huntington s disease as a tool to study store operated calcium entry drug targeting |
| topic | store-operated calcium channels SOC Huntington’s disease neurodegeneration EVP4593 iPS cells |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.00696/full |
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