title: Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor.
abstract: Aggresomes are cytoplasmic inclusions which are localized at the microtubule organizing center (MTOC) as a result of induced proteasome inhibition, stress or over-expression of certain proteins. Aggresomes are linked to the pathogenesis of many neurodegenerative diseases. Here we studied whether amyloid precursor protein (APP), a type-I transmembrane glycoprotein, is localized in aggresomes after exposure to stress condition. Using confocal microscopy we found that APP is located in aggresomes and co-localized with vimentin, γ-tubulin, 20S and ubiquitin at the MTOC in response to proteasome dysfunction. An interaction between vimentin and APP was found after proteasome inhibition suggesting that APP is an additional protein constituent of aggresomes. Suppression of the proteasome system in APP-HEK293 cells overexpressing APP or transfected with APP Swedish mutation caused an accumulation of stable, detergent-insoluble forms of APP containing poly-ubiquitinated proteins. In addition, brain homogenates from transgenic mice expressing human APP with the Arctic mutation demonstrated an interaction between APP and the aggresomal-marker vimentin. These data suggest that malfunctioning of the proteasome system caused by mutation or overexpression of pathological or non-pathological proteins may lead to the accumulation of stable aggresomes, perhaps contributing to the neurodegeneration.
authors.affiliation: Department of Physiology, The Wenner-Gren Institute Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden.
authors.forename: Nodi
authors.initials: N
authors.lastname: Dehvari
authors.forename: Tapan
authors.initials: T
authors.lastname: Mahmud
authors.forename: Johanna
authors.initials: J
authors.lastname: Persson
authors.forename: Tore
authors.initials: T
authors.lastname: Bengtsson
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Annica
authors.initials: A
authors.lastname: Rönnbäck
authors.forename: Homira
authors.initials: H
authors.lastname: Behbahani
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D061988:Proteasome Inhibitors
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors