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Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs

Spinocerebellar ataxia type 3 (SCA3) is characterized by the over-repetitive CAG codon in the ataxin-3 gene (ATXN3), which encodes the mutant ATXN3 protein. The pathological defects of SCA3 such as the impaired aggresomes, autophagy, and the proteasome have been reported previously. To date, no effe...

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Autores principales: Yang, Hsin-Han, Chiang, I-Tsang, Liu, Jen-Wei, Hsieh, Jeanne, Lee, Jui-Hao, Lu, Huai-En, Tso, Hwa-Sung, Deng, Yu-Chen, Kao, Jo-Chi, Wu, Jhen-Rong, Harn, Horng-Jyh, Chiou, Tzyy-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836169/
https://www.ncbi.nlm.nih.gov/pubmed/35163312
http://dx.doi.org/10.3390/ijms23031391
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author Yang, Hsin-Han
Chiang, I-Tsang
Liu, Jen-Wei
Hsieh, Jeanne
Lee, Jui-Hao
Lu, Huai-En
Tso, Hwa-Sung
Deng, Yu-Chen
Kao, Jo-Chi
Wu, Jhen-Rong
Harn, Horng-Jyh
Chiou, Tzyy-Wen
author_facet Yang, Hsin-Han
Chiang, I-Tsang
Liu, Jen-Wei
Hsieh, Jeanne
Lee, Jui-Hao
Lu, Huai-En
Tso, Hwa-Sung
Deng, Yu-Chen
Kao, Jo-Chi
Wu, Jhen-Rong
Harn, Horng-Jyh
Chiou, Tzyy-Wen
author_sort Yang, Hsin-Han
collection PubMed
description Spinocerebellar ataxia type 3 (SCA3) is characterized by the over-repetitive CAG codon in the ataxin-3 gene (ATXN3), which encodes the mutant ATXN3 protein. The pathological defects of SCA3 such as the impaired aggresomes, autophagy, and the proteasome have been reported previously. To date, no effective treatment is available for SCA3 disease. This study aimed to study anti-excitotoxic effects of n-butylidenephthalide by chemically insulted Purkinje progenitor cells derived from SCA3 iPSCs. We successfully generated Purkinje progenitor cells (PPs) from SCA3 patient-derived iPSCs. The PPs, expressing both neural and Purkinje progenitor’s markers, were acquired after 35 days of differentiation. In comparison with the PPs derived from control iPSCs, SCA3 iPSCs-derived PPs were more sensitive to the excitotoxicity induced by quinolinic acid (QA). The observations of QA-treated SCA3 PPs showing neural degeneration including neurite shrinkage and cell number decrease could be used to quickly and efficiently identify drug candidates. Given that the QA-induced neural cell death of SCA3 PPs was established, the activity of calpain in SCA3 PPs was revealed. Furthermore, the expression of cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptotic pathway, and the accumulation of ATXN3 proteolytic fragments were observed. When SCA3 PPs were treated with n-butylidenephthalide (n-BP), upregulated expression of calpain 2 and concurrent decreased level of calpastatin could be reversed, and the overall calpain activity was accordingly suppressed. Such findings reveal that n-BP could not only inhibit the cleavage of ATXN3 but also protect the QA-induced excitotoxicity from the Purkinje progenitor loss.
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spelling pubmed-88361692022-02-12 Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs Yang, Hsin-Han Chiang, I-Tsang Liu, Jen-Wei Hsieh, Jeanne Lee, Jui-Hao Lu, Huai-En Tso, Hwa-Sung Deng, Yu-Chen Kao, Jo-Chi Wu, Jhen-Rong Harn, Horng-Jyh Chiou, Tzyy-Wen Int J Mol Sci Article Spinocerebellar ataxia type 3 (SCA3) is characterized by the over-repetitive CAG codon in the ataxin-3 gene (ATXN3), which encodes the mutant ATXN3 protein. The pathological defects of SCA3 such as the impaired aggresomes, autophagy, and the proteasome have been reported previously. To date, no effective treatment is available for SCA3 disease. This study aimed to study anti-excitotoxic effects of n-butylidenephthalide by chemically insulted Purkinje progenitor cells derived from SCA3 iPSCs. We successfully generated Purkinje progenitor cells (PPs) from SCA3 patient-derived iPSCs. The PPs, expressing both neural and Purkinje progenitor’s markers, were acquired after 35 days of differentiation. In comparison with the PPs derived from control iPSCs, SCA3 iPSCs-derived PPs were more sensitive to the excitotoxicity induced by quinolinic acid (QA). The observations of QA-treated SCA3 PPs showing neural degeneration including neurite shrinkage and cell number decrease could be used to quickly and efficiently identify drug candidates. Given that the QA-induced neural cell death of SCA3 PPs was established, the activity of calpain in SCA3 PPs was revealed. Furthermore, the expression of cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptotic pathway, and the accumulation of ATXN3 proteolytic fragments were observed. When SCA3 PPs were treated with n-butylidenephthalide (n-BP), upregulated expression of calpain 2 and concurrent decreased level of calpastatin could be reversed, and the overall calpain activity was accordingly suppressed. Such findings reveal that n-BP could not only inhibit the cleavage of ATXN3 but also protect the QA-induced excitotoxicity from the Purkinje progenitor loss. MDPI 2022-01-26 /pmc/articles/PMC8836169/ /pubmed/35163312 http://dx.doi.org/10.3390/ijms23031391 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Hsin-Han
Chiang, I-Tsang
Liu, Jen-Wei
Hsieh, Jeanne
Lee, Jui-Hao
Lu, Huai-En
Tso, Hwa-Sung
Deng, Yu-Chen
Kao, Jo-Chi
Wu, Jhen-Rong
Harn, Horng-Jyh
Chiou, Tzyy-Wen
Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title_full Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title_fullStr Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title_full_unstemmed Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title_short Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs
title_sort anti-excitotoxic effects of n-butylidenephthalide revealed by chemically insulted purkinje progenitor cells derived from sca3 ipscs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836169/
https://www.ncbi.nlm.nih.gov/pubmed/35163312
http://dx.doi.org/10.3390/ijms23031391
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