title: Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease.
abstract: 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-β precursor protein (AβPP). 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 AβPP gene or 717 valine-to-glycine AβPP-mutated gene. The over-expression of the AβPP 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-β(42) 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 Aβ(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional.
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, 62032 Camerino, Italy. valentina.cecarini@unicam.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecarini
authors.forename: Laura
authors.initials: L
authors.lastname: Bonfili
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.forename: Matteo
authors.initials: M
authors.lastname: Mozzicafreddo
authors.forename: Giacomo
authors.initials: G
authors.lastname: Rossi
authors.forename: Laura
authors.initials: L
authors.lastname: Buizza
authors.forename: Daniela
authors.initials: D
authors.lastname: Uberti
authors.forename: Mauro
authors.initials: M
authors.lastname: Angeletti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Eleuteri
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D025801:Ubiquitin; C075222:amyloid beta-protein (1-42); D046988:Proteasome Endopeptidase Complex