α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP

Journal article

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: Roberts, HL; Schneider, BL; Brown, DR

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS ONE
• Volume: 12
• Issue: 2
• Article number: 0171925
• Publication date: 2017-02-10
• Acceptance date: 2017-01-29
• DOI: 10.1371/journal.pone.0171925
• EISSN: 1932-6203
• Pmid: 28187176
• Language: English