Protein repertoire impact of Ubiquitin-Proteasome System impairment: insight into the protective role of beta-estradiol |
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| Authors: | D'Alessandro Annamaria D'Aguanno Simona Cencioni Maria Teresa Pieroni Luisa Diamantini Adamo Battistini Luca Longone Patrizia Spalloni Alida De Laurenzi Vincenzo Bernardini Sergio Federici Giorgio Urbani Andrea |
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| Affiliation: | a Department of Internal Medicine, University of Rome “Tor Vergata”, Faculty of Medicine and Surgery, Via Montpellier, 1, 00133-Rome, Italyb Santa Lucia Foundation-IRCCS, Via del Fosso di Fiorano, 64, 00143-Rome, Italyc Department of Biomedical Science, University“ G. D'Annunzio”, Via dei Vestini 31, 66013-Chieti, Italyd Children's Hospital “Bambino Gesù”-IRCCS, Piazza Sant'Onofrio, 4, 00165-Rome, Vatican City State |
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| Abstract: | The Ubiquitin-Proteasome System (UPS) and the Autophagy-Lysosome Pathways (ALP) are key mechanisms for cellular homeostasis sustenance and protein clearance. A wide number of Neurodegenerative Diseases (NDs) are tied with UPS impairment and have been also described as proteinopathies caused by aggregate-prone proteins, not efficiently removed by proteasome. Despite the large knowledge on proteasome biological role, molecular mechanisms associated with its impairment are still blur. We have pursued a comprehensive proteomic investigation to evaluate the phenotypic rearrangements in protein repertoires associated with a UPS blockage. Different functional proteomic approaches have been employed to tackle UPS impairment impact on human NeuroBlastoma (NB) cell lines responsive to proteasome inhibition by Epoxomicin. 2-Dimensional Electrophoresis (2-DE) separation combined with Mass Spectrometry and Shotgun Proteomics experiments have been employed to design a thorough picture of protein profile. Unsupervised meta-analysis of the collected proteomic data revealed that all the identified proteins relate each other in a functional network centered on beta-estradiol. Moreover we showed that treatment of cells with beta-estradiol resulted in aggregate removal and increased cell survival due to activation of the autophagic pathway. Our data may provide the molecular basis for the use of beta-estradiol in neurodegenerative disorders by induction of protein aggregate removal. |
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| Keywords: | 2-DE, 2-Dimensional Electrophoresis 7-ADD, 7-Amino-actinomycin ALP, Autophagy-Lysosome Pathways ALS, Amyotrophic Lateral Sclerosis AV, Annexin V BEH, Bridged Ethyl Hybrid CMA, Chaperone-Mediated Autophagy ECL, Enhanced ChemiLuminescence EMRT, Exact Mass Retention Time ESI-Q-TOF, Electrospray-Quadrupole-Time Of Flight FACS, Fluorescence Activated Cell Sorting HCCA, α-Cyano-4-HydroxyCinnamic Acid HSPs, Heat Shock Proteins HSP10 (60, 70, 90, etc.), Heat Shock Protein 10 kDa (60, 70, 90, etc.) IEF, IsoElectroFocusing IPA, Ingenuity Pathways Analysis IPKB, Ingenuity Pathways Knowledge Base LC3, microtubule-associated protein 1 Light Chain 3 LC-MS/MS, Liquid Chromatography coupled with tandem MS LC-MSE, LC-MS using simultaneous acquisition of exact mass at high and low collision energy MALDI-TOF, Matrix-Assisted Laser Desorption/Ionization MPRs, Mannose 6-Phosphate Receptors MS-PMF, Mass Spectrometry-Peptide Mass Fingerprinting Mr, Molecular ratio NB, NeuroBlastoma NDs, Neurodegenerative Diseases NIH, National Institutes of Health Op18, Oncoprotein 18 PANTHER, Protein ANalysis THrough Evolutionary Relationships PD, Parkinson's disease pI, Isoelectric point PI, Propidium Iodide PIs, Proteasome Inhibitors PLGS, ProteinLynx Global SERVER ROI, Region of Interest RP, Reversed Phase TCA, TriChloroacetic acid TIP47, Tail Interacting Protein47-kDa UPS, Ubiquitin-Proteasome System VGF, VGF nerve growth factor inducible protein |
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