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A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells

Authors Hsieh C, Lee L, Leong W, Yang T, Yao C, Fang K

Received 3 May 2016

Accepted for publication 15 June 2016

Published 14 September 2016 Volume 2016:10 Pages 2947—2957

DOI https://doi.org/10.2147/DDDT.S111903

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5

Editor who approved publication: Prof. Dr. Wei Duan


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

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