Atriazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells

Chang Heng Hsieh, Li Ching Lee, Wai Yin Leong, Tsai Chen Yang, Ching-Fa Yao, Kang Fang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2947-2957
Number of pages11
JournalDrug Design, Development and Therapy
Volume10
DOIs
Publication statusPublished - 2016 Sep 14

Fingerprint

Autophagy
Mitogen-Activated Protein Kinase 8
Trinucleotide Repeat Expansion
Triazoles
JNK Mitogen-Activated Protein Kinases
Glutamine
Neuroblastoma
Fluorescence
polyglutamine
Genes
Proteins
Beclin-1

Keywords

  • Aggregates clearance
  • Autophagic flux
  • Green fluorescence protein
  • JNK pathway
  • Neuronal disorders
  • Polyglutamine
  • Triazole

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Atriazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells. / Hsieh, Chang Heng; Lee, Li Ching; Leong, Wai Yin; Yang, Tsai Chen; Yao, Ching-Fa; Fang, Kang.

In: Drug Design, Development and Therapy, Vol. 10, 14.09.2016, p. 2947-2957.

Research output: Contribution to journalArticle

Hsieh, Chang Heng ; Lee, Li Ching ; Leong, Wai Yin ; Yang, Tsai Chen ; Yao, Ching-Fa ; Fang, Kang. / Atriazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells. In: Drug Design, Development and Therapy. 2016 ; Vol. 10. pp. 2947-2957.
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