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?-Synuclein increases ?-amyloid secretion by promoting ?-/?-secretase processing of APP.

ABSTRACT: ?-Synuclein misfolding and aggregation is often accompanied by ?-amyloid deposition in some neurodegenerative diseases. We hypothesised that ?-synuclein promotes ?-amyloid production from APP. ?-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant ?-synuclein. ?-Secretase activity and ?-secretase expression were also measured. We show that ?-synuclein expression induces ?-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of ?-synuclein potentiate APP amyloidogenic processing. ?-Secretase activity was not enhanced by wildtype ?-synuclein expression, however ?-secretase protein levels were induced. Furthermore, a correlation between ?-synuclein and ?-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of ?-synuclein on neuronal cell ?-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that ?-synuclein promotes ?-amyloid formation by modulating ?-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.

SUBMITTER: Roberts HL

PROVIDER: S-EPMC5302447 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Roberts Hazel L HL Schneider Bernard L BL Brown David R DR

PloS one 20170210 2

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 ...[more]

PMID: 28187176

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Project description:The amyloid β-peptide (Aβ) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid β protein-precursor (APP CTFβ) by the γ-secretase complex. This processing produces Aβ ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of Aβ peptides is the result of successive γ-secretase cleavages, with endoproteolysis first occurring at the ε sites to generate Aβ48 or Aβ49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of Aβ: the primary Aβ49-46-43-40 line and a minor Aβ48-45-42-38 line. The major secreted Aβ species are Aβ40 and Aβ42, and an increased proportion of the longer, aggregation-prone Aβ42 compared to Aβ40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ε site endoproteolysis and carboxypeptidase trimming of CTFβ by γ-secretase. We determined that the C-terminal negative charge of the intermediate Aβ49 does not play a role in its trimming by γ-secretase. Peptidomimetic probes suggest that γ-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ε sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ε cleavage of CTFβ. We also show that instability of the CTFβ TMD helix near the ε site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by γ-secretase. In addition, we found that CTFβ dimers are not endoproteolyzed by γ-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ε cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

Dataset Information

?-Synuclein increases ?-amyloid secretion by promoting ?-/?-secretase processing of APP.

Publications

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

Similar Datasets

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