A triazole derivative elicits autophagic clearance of polyglutamine aggregation in neuronal cells.
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.
Department of Life Science.
Chang Heng
CH
Hsieh
Department of Life Science.
Li-Ching
LC
Lee
Department of Life Science.
Wai-Yin
WY
Leong
Department of Life Science.
Tsai-Chen
TC
Yang
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
Ching-Fa
CF
Yao
Department of Life Science.
Kang
K
Fang
D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology
D018942:Macrolides; D009419:Nerve Tissue Proteins; D010455:Peptides; D014230:Triazoles; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C040929:bafilomycin A1
JNK pathway; aggregates clearance; autophagic flux; green fluorescence protein; neuronal disorders; polyglutamine; triazole
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