Differential ERK activation during autophagy induced by europium hydroxide nanorods and trehalose: Maximum clearance of huntingtin aggregates through combined treatment.

Abstract	Accelerating the clearance of intracellular protein aggregates through elevation of autophagy represents a viable approach for the treatment of neurodegenerative diseases. In our earlier report, we have demonstrated the enhanced degradation of mutant huntingtin protein aggregates through autophagy process induced by europium hydroxide nanorods [EHNs: Eu(III)(OH)3], but the underlying molecular mechanism of EHNs mediated autophagy was unclear. The present report reveals that EHNs induced autophagy does not follow the classical AKT-mTOR and AMPK signaling pathways. The inhibition of ERK1/2 phosphorylation using the specific MEK inhibitor U0126 partially abrogates the autophagy as well as the clearance of mutant huntingtin protein aggregates mediated by EHNs suggesting that nanorods stimulate the activation of MEK/ERK1/2 signaling pathway during autophagy process. In contrast, another mTOR-independent autophagy inducer trehalose has been found to induce autophagy without activating ERK1/2 signaling pathway. Interestingly, the combined treatment of EHNs and trehalose leads to more degradation of mutant huntingtin protein aggregates than that obtained with single treatment of either nanorods or trehalose. Our results demonstrate the rational that further enhanced clearance of intracellular protein aggregates, needed for diverse neurodegenerative diseases, may be achieved through the combined treatment of two or more autophagy inducers, which stimulate autophagy through different signaling pathways.
Authors	Peng-Fei Wei, Pei-Pei Jin, Ayan Kumar Barui, Yi Hu, Li Zhang, Ji-Qian Zhang, Shan-Shan Shi, Hou-Rui Zhang, Jun Lin, Wei Zhou, Yun-Jiao Zhang, Ren-Quan Ruan, Chitta Ranjan Patra, Long-Ping Wen
Journal	Biomaterials (Biomaterials) Vol. 73 Pg. 160-74 (Dec 2015) ISSN: 1878-5905 [Electronic] Netherlands
PMID	26409001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References	ATG5 protein, human Androstadienes Autophagy-Related Protein 5 Butadienes HTT protein, human Huntingtin Protein Hydroxides Macrolides Microtubule-Associated Proteins Nerve Tissue Proteins Nitriles RNA, Small Interfering U 0126 Green Fluorescent Proteins Europium 3-methyladenine Chloroquine bafilomycin A1 Trehalose MTOR protein, human TOR Serine-Threonine Kinases Extracellular Signal-Regulated MAP Kinases Adenine Wortmannin
Topics	Adenine (analogs & derivatives, chemistry) Androstadienes (chemistry) Animals Autophagy Autophagy-Related Protein 5 Butadienes (chemistry) Cell Line, Tumor Cell Survival Chloroquine (chemistry) Europium (chemistry) Extracellular Signal-Regulated MAP Kinases (metabolism) Green Fluorescent Proteins (metabolism) HeLa Cells Humans Huntingtin Protein Hydroxides (chemistry) Lysosomes (metabolism) Macrolides (chemistry) Mice Microscopy, Fluorescence Microtubule-Associated Proteins (metabolism) Nanotubes (chemistry) Nerve Tissue Proteins (chemistry) Neurodegenerative Diseases (embryology, metabolism) Nitriles (chemistry) Phagosomes (chemistry) Phosphorylation RNA, Small Interfering (metabolism) Signal Transduction TOR Serine-Threonine Kinases (metabolism) Trehalose (chemistry) Wortmannin

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