Protein repertoire impact of Ubiquitin-Proteasome System impairment: insight into the protective role of beta-estradiol.

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.

• Authors: Annamaria D'Alessandro, Simona D'Aguanno, Maria Teresa Cencioni, Luisa Pieroni, Adamo Diamantini, Luca Battistini, Patrizia Longone, Alida Spalloni, Vincenzo De Laurenzi, Sergio Bernardini, Giorgio Federici, Andrea Urbani
• Journal: Journal of proteomics (J Proteomics) Vol. 75 Issue 4 Pg. 1440-53 (Feb 02 2012) ISSN: 1876-7737 [Electronic] Netherlands
• PMID: 22146475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Ubiquitin
• Estradiol
• Proteasome Endopeptidase Complex

Topics

• Autophagy
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Electrophoresis, Gel, Two-Dimensional (methods)
• Estradiol (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Lysosomes (metabolism)
• Mass Spectrometry (methods)
• Models, Biological
• Neuroblastoma (metabolism)
• Neurodegenerative Diseases (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteomics (methods)
• Ubiquitin (metabolism)