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.
Highlights
Protein misfolding is an integral feature of age-related neurodegenerative diseases, and stereotypically involves just a handful of conformationally flexible proteins
Steap3 plasmid was generated by cloning the human Steap3 sequence (RefSeq accession number NG_042823.1) into a pcDNA 3.1 (+) vector. pFR-Luciferase reporter vector containing firefly (Photinus pyralis) luciferase gene, with a synthetic promoter of yeast Gal4 upstream activation sequence in 5 tandem repeats upstream of a minimal TATA box, Alpha-synuclein and beta-amyloid was from Promega. phRL thymidine kinase vector containing sea pansy (Renilla reniformis) luciferase gene, under control of the herpes simplex virus-TK promoter, was from Promega. pRC-CMV-APP695-Gal4 (APP-Gal4) and pSec-Tag2-Notch3Gal4 (Notch-Gal4) were kindly provided by Dr Robert J
APP695 was overexpressed in SH-SY5Ys, to ascertain the effect on α-synuclein protein. α-Synuclein protein levels were unaltered (Fig 1B)
Summary
Protein misfolding is an integral feature of age-related neurodegenerative diseases, and stereotypically involves just a handful of conformationally flexible proteins. Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are defined by intracellular inclusions of aggregated αsynuclein, known as ‘Lewy bodies’ [1]. Alzheimer’s disease (AD) brains, in contrast, predominantly exhibit extracellular amyloid plaques of β-amyloid, and intracellular inclusions of tau protein [2,3,4,5]. A sizeable proportion of patients classified as DLB or AD have both α-synuclein and β-amyloid aggregates [6,7,8,9,10,11,12,13,14], leading to the suggestion that the two proteins may be somehow linked [15]. 30% of PD patients have dementia, which may rise to 70–80% within a decade of PD diagnosis [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
