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

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.

Graphical abstractNeurodegenerative Diseases have been described as proteinopathies caused by aggregate-prone proteins not efficiently removed by proteasome. In this study, to evaluate rearrangements in protein repertoires associated with UPS blockage, we have pursued a comprehensive proteomic investigation coupled to unsupervised meta-analysis revealing a functional network centered on beta-estradiol. Interestingly we have demonstrated that estradiol pre-treatment result in aggregate removal and increased cell survival by induction of autophagic pathway.Figure optionsDownload full-size imageDownload high-quality image (250 K)Download as PowerPoint slideHighlights► Proteomics on cell models responsiveness to PIs enable the elucidation of the molecular mechanism of proteinopathies. ► Meta-analysis of proteomic data disclose functional networks involved in UPS impairment centered on estradiol. ► Experimental biological evidences display the involvement of estradiol in the aggresome removal by autophagy induction. ► This investigation suggest estradiol potential therapeutic use in proteinopathies by protein aggregate removal induction.