A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells
Chang Heng Hsieh,1 Li-Ching Lee,1 Wai-Yin Leong,1 Tsai-Chen Yang,1 Ching-Fa Yao,2 Kang Fang1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan Abstract: Trinucleotide CAG repeat expansion in the coding region of genes has a propensity to form...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2016-09-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/a-triazole-derivative-elicits-autophagic-clearance-of-polyglutamine-ag-peer-reviewed-article-DDDT |
| _version_ | 1818893907004489728 |
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| author | Hsieh CH Lee LC Leong WY Yang TC Yao CF Fang K |
| author_facet | Hsieh CH Lee LC Leong WY Yang TC Yao CF Fang K |
| author_sort | Hsieh CH |
| collection | DOAJ |
| description | Chang Heng Hsieh,1 Li-Ching Lee,1 Wai-Yin Leong,1 Tsai-Chen Yang,1 Ching-Fa Yao,2 Kang Fang1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan Abstract: Trinucleotide CAG repeat expansion in the coding region of genes has a propensity to form polyglutamine (polyQ) aggregates that contribute to neuronal disorders. Strategies in elevating autophagy to disintegrate the insoluble aggregates without injuring cells have become a major goal for therapy. In this work, a triazole derivative, OC-13, was found accelerating autophagic clearance of polyQ aggregation in human neuroblastoma cells following induction of the enhanced green fluorescence-conjugated chimeric protein that enclosed 79 polyQ repeats (Q79-EGFP). OC-13 accelerated autophagy development and removed nuclear Q79-EGFP aggregates. The increase of Beclin-1, turnover of LC3-I to LC3-II and degradation of p62 supported autophagy activation. Pretreatment of autophagy inhibitor, bafilomycin A1, not only suppressed autophagolysome fusion, but also impeded aggregate eradication. The study also showed that c-Jun N-terminal kinase/Beclin-1 pathway was activated during OC-13 treatment and c-Jun N-terminal kinase inhibitor impaired autophagy and final breakdown. Autophagic clearance of the insoluble aggregates demonstrated the feasibility of OC-13 in alleviating neuronal disorders because of expanded glutamine stretches. Keywords: autophagic flux, polyglutamine, aggregates clearance, triazole, JNK pathway, neuronal disorders, green fluorescence protein |
| first_indexed | 2024-12-19T18:20:03Z |
| format | Article |
| id | doaj.art-8b8f4d5f953b4d0b8555be405651a399 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-19T18:20:03Z |
| publishDate | 2016-09-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-8b8f4d5f953b4d0b8555be405651a3992022-12-21T20:11:00ZengDove Medical PressDrug Design, Development and Therapy1177-88812016-09-01Volume 102947295728914A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cellsHsieh CHLee LCLeong WYYang TCYao CFFang KChang Heng Hsieh,1 Li-Ching Lee,1 Wai-Yin Leong,1 Tsai-Chen Yang,1 Ching-Fa Yao,2 Kang Fang1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan Abstract: Trinucleotide CAG repeat expansion in the coding region of genes has a propensity to form polyglutamine (polyQ) aggregates that contribute to neuronal disorders. Strategies in elevating autophagy to disintegrate the insoluble aggregates without injuring cells have become a major goal for therapy. In this work, a triazole derivative, OC-13, was found accelerating autophagic clearance of polyQ aggregation in human neuroblastoma cells following induction of the enhanced green fluorescence-conjugated chimeric protein that enclosed 79 polyQ repeats (Q79-EGFP). OC-13 accelerated autophagy development and removed nuclear Q79-EGFP aggregates. The increase of Beclin-1, turnover of LC3-I to LC3-II and degradation of p62 supported autophagy activation. Pretreatment of autophagy inhibitor, bafilomycin A1, not only suppressed autophagolysome fusion, but also impeded aggregate eradication. The study also showed that c-Jun N-terminal kinase/Beclin-1 pathway was activated during OC-13 treatment and c-Jun N-terminal kinase inhibitor impaired autophagy and final breakdown. Autophagic clearance of the insoluble aggregates demonstrated the feasibility of OC-13 in alleviating neuronal disorders because of expanded glutamine stretches. Keywords: autophagic flux, polyglutamine, aggregates clearance, triazole, JNK pathway, neuronal disorders, green fluorescence proteinhttps://www.dovepress.com/a-triazole-derivative-elicits-autophagic-clearance-of-polyglutamine-ag-peer-reviewed-article-DDDTautophagypolyglutamineaggregates clearance |
| spellingShingle | Hsieh CH Lee LC Leong WY Yang TC Yao CF Fang K A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells Drug Design, Development and Therapy autophagy polyglutamine aggregates clearance |
| title | A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| title_full | A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| title_fullStr | A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| title_full_unstemmed | A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| title_short | A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| title_sort | triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
| topic | autophagy polyglutamine aggregates clearance |
| url | https://www.dovepress.com/a-triazole-derivative-elicits-autophagic-clearance-of-polyglutamine-ag-peer-reviewed-article-DDDT |
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