title: Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson's disease.
abstract: Accumulation of misfolded proteins in the endoplasmic reticulum (ER) is the main event leading to the induction of the ER stress-related unfolded protein response (UPR). Recent postmortem evaluation, showing that the UPR pathway is activated in nigral dopaminergic neurons bearing α-synuclein inclusions in the brain of Parkinson's disease (PD) patients, suggests that the activation of the UPR may be induced by the accumulation of α-synuclein. In this study, we show that the misfolded protein-sensor/UPR activator glucose-regulated protein 78/immunoglobulin heavy chain-binding protein was bound to α-synuclein and was increased in 'in vitro' and 'in vivo' models showing aggregated α-synuclein accumulation. Moreover, α-synuclein accumulation induced the expression of the UPR-related activating transcription factor 4/cAMP-responsive element-2. These findings indicate that activation of the UPR pathway in the PD brain is associated with α-synuclein accumulation occurring in part within the ER.
authors.affiliation: Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy. bellucci@med.unibs.it
authors.forename: Arianna
authors.initials: A
authors.lastname: Bellucci
authors.forename: Laura
authors.initials: L
authors.lastname: Navarria
authors.forename: Michela
authors.initials: M
authors.lastname: Zaltieri
authors.forename: Elisa
authors.initials: E
authors.lastname: Falarti
authors.forename: Serena
authors.initials: S
authors.lastname: Bodei
authors.forename: Sandra
authors.initials: S
authors.lastname: Sigala
authors.forename: Leontino
authors.initials: L
authors.lastname: Battistin
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Spillantini
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Spano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein