α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP.
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 overexpre...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171925&type=printable |
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| author | Hazel L Roberts Bernard L Schneider David R Brown |
| author_facet | Hazel L Roberts Bernard L Schneider David R Brown |
| author_sort | Hazel L Roberts |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a521125127db4c19b5e00e42d0494224 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-a521125127db4c19b5e00e42d04942242025-08-20T02:46:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017192510.1371/journal.pone.0171925α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP.Hazel L RobertsBernard L SchneiderDavid R Brownα-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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171925&type=printable |
| spellingShingle | Hazel L Roberts Bernard L Schneider David R Brown α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. PLoS ONE |
| title | α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. |
| title_full | α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. |
| title_fullStr | α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. |
| title_full_unstemmed | α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. |
| title_short | α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. |
| title_sort | α synuclein increases β amyloid secretion by promoting β γ secretase processing of app |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171925&type=printable |
| work_keys_str_mv | AT hazellroberts asynucleinincreasesbamyloidsecretionbypromotingbgsecretaseprocessingofapp AT bernardlschneider asynucleinincreasesbamyloidsecretionbypromotingbgsecretaseprocessingofapp AT davidrbrown asynucleinincreasesbamyloidsecretionbypromotingbgsecretaseprocessingofapp |