Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease

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• 作者：Valentina Cecarini ; Laura Bonfili ; Massimiliano Cuccioloni ; Matteo Mozzicafreddo ; Giacomo Rossi ; Laura Buizza ; Daniela Uberti ; Mauro Angeletti ; Anna Maria Eleuteri
• 关键词：A¦ÂPP ; amyloid-¦Â precursor protein ; A¦Â40 ; amyloid-¦Â (1&ndash ; 40) ; A¦Â42 ; amyloid-¦Â (1&ndash ; 42) ; UPS ; ubiquitin&ndash ; proteasome system ; HDAC6 ; histone deacetylase 6 ; ChT-L ; chymotrypsin-like ; T-L ; trypsin-like ; PGPH ; peptidylglutamyl-peptide hydrolyz
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：1822
• 期：11
• 页码：1741-1751
• 全文大小：1524 K

文摘

Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-¦Â precursor protein (A¦ÂPP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type A¦ÂPP gene or 717 valine-to-glycine A¦ÂPP-mutated gene. The over-expression of the A¦ÂPP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-¦Â₄₂ oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an A¦Â₄₂ threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional.