title: α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP.
abstract: α-Synuclein misfolding and aggregation is often accompanied by β-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes β-amyloid production from APP. β-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and β-secretase expression were also measured. We show that α-synuclein expression induces β-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of α-synuclein potentiate APP amyloidogenic processing. γ-Secretase activity was not enhanced by wildtype α-synuclein expression, however β-secretase protein levels were induced. Furthermore, a correlation between α-synuclein and β-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of α-synuclein on neuronal cell β-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that α-synuclein promotes β-amyloid formation by modulating β-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.
authors.affiliation: Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
authors.forename: Hazel L
authors.initials: HL
authors.lastname: Roberts
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Brown
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D015513:Oncogene Proteins; D051844:alpha-Synuclein; D007501:Iron; D010088:Oxidoreductases; C486677:STEAP3 protein, human; D053829:Amyloid Precursor Protein Secretases