title: 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.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wei
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Jin
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India.
authors.forename: Ayan Kumar
authors.initials: AK
authors.lastname: Barui
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, Anhui Medical University, 230022 Hefei, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Ji-Qian
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Shi
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Hou-Rui
authors.initials: HR
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Yun-Jiao
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Ren-Quan
authors.initials: RQ
authors.lastname: Ruan
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India. Electronic address: patra.chitta@gmail.com.
authors.forename: Chitta Ranjan
authors.initials: CR
authors.lastname: Patra
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China. Electronic address: lpwen@ustc.edu.cn.
authors.forename: Long-Ping
authors.initials: LP
authors.lastname: Wen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000730:Androstadienes / Q000737:chemistry; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002070:Butadienes / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D002738:Chloroquine / Q000737:chemistry; D005063:Europium / Q000737:chemistry*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006878:Hydroxides / Q000737:chemistry*; D008247:Lysosomes / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D043942:Nanotubes / Q000737:chemistry*; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000196:embryology / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry; D010588:Phagosomes / Q000737:chemistry; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014199:Trehalose / Q000737:chemistry*; D000077191:Wortmannin
chemical_list: C502778:ATG5 protein, human; D000730:Androstadienes; D000071187:Autophagy-Related Protein 5; D002070:Butadienes; C086055:HTT protein, human; D000071058:Huntingtin Protein; D006878:Hydroxides; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D049452:Green Fluorescent Proteins; D005063:Europium; C025946:3-methyladenine; D002738:Chloroquine; C040929:bafilomycin A1; D014199:Trehalose; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000225:Adenine; D000077191:Wortmannin
keywords: Autophagy; Europium hydroxide nanorods [EHNs: Eu(III)(OH)(3)]; Huntingtin protein aggregates; Trehalose; mTOR; p-ERK1/2