title: Expanded and Wild-type Ataxin-3 Modify the Redox Status of SH-SY5Y Cells Overexpressing α-Synuclein.
abstract: Neurodegenerative diseases are considered to be distinct clinical entities, although they share the formation of proteinaceous aggregates and several neuropathological mechanisms. Increasing evidence suggest a possible interaction between proteins that have been classically associated to distinct neurodegenerative diseases. Thus, common molecular and cellular pathways might explain similarities between disease phenotypes. Interestingly, the characteristic Parkinson's disease (PD) phenotype linked to bradykinesia is also a clinical presentation of other neurodegenerative diseases. An example is Machado-Joseph disease (MJD), with some patients presenting parkinsonism and a positive response to levodopa (L-DOPA). Protein aggregates positive for α-synuclein (α-Syn), a protein associated with PD, in the substantia nigra of MJD models made us hypothesize a putative additive biological effect induced by expression of α-Syn and ataxin-3 (Atx3), the protein affected in MJD. Hence, in this study we analysed the influence of these two proteins (α-Syn and wild-type or mutant Atx3) on modified redox signaling, a pathological process potentially linked to both diseases, and also the impact of exposure to iron and rotenone in SH-SY5Y neuroblastoma cells. Our results show that both α-Syn and mutant Atx3 overexpression per se increased oxidation of dichlorodihydrofluorescein (DCFH2), and co-expression of these proteins exhibited additive effect on intracellular oxidation, with no correlation with apoptotic features. Mutant Atx3 and α-Syn also potentiated altered redox status induced by iron and rotenone, a hint to how these proteins might influence neuronal dysfunction under pro-oxidant conditions. We further show that overexpression of wild-type Atx3 decreased intracellular DCFH2oxidation, possibly exerting a neuroprotective role.
authors.affiliation: Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Noronha
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Perfeito
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Laço
authors.affiliation: Klinik und Poliklinik für Neurologie, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.affiliation: Faculty of Medicine, University of Coimbra, Coimbra, Portugal. acrego@cnc.uc.pt.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. acrego@cnc.uc.pt.|Faculty of Medicine, and Center for Neuroscience and Cell Biology, University of Coimbra, (Pólo I) Rua Larga, 3004-504, Coimbra, Portugal. acrego@cnc.uc.pt.
authors.forename: A Cristina
authors.identifier: http://orcid.org/0000-0003-0700-3776
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000067699:Ataxin-3 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012097:Repressor Proteins; D051844:alpha-Synuclein; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: Alpha-synuclein; Ataxin-3; Cellular oxidation; Iron; Machado–Joseph disease; Parkinson’s disease; Rotenone