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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doaj-8b8f4d5f953b4d0b8555be405651a3992020-11-24T21:02:18ZengDove 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 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hsieh CH Lee LC Leong WY Yang TC Yao CF Fang K |
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 |
author_facet |
Hsieh CH Lee LC Leong WY Yang TC Yao CF Fang K |
author_sort |
Hsieh CH |
title |
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_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_sort |
triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells |
publisher |
Dove Medical Press |
series |
Drug Design, Development and Therapy |
issn |
1177-8881 |
publishDate |
2016-09-01 |
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 |
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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