Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.
BACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics dem...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4049638?pdf=render |
id |
doaj-55608c07c78a44c49f2eb7df00257af8 |
---|---|
record_format |
Article |
spelling |
doaj-55608c07c78a44c49f2eb7df00257af82020-11-25T00:47:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e9890610.1371/journal.pone.0098906Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.Georg Sebastian NüblingJohannes LevinBenedikt BaderStefan LorenzlAndreas HillmerTobias HögenFrits KampArmin GieseBACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. METHODS: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. RESULTS: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+) induced asyn129E oligomers and markedly reduced in Al(3+) induced oligomers. CONCLUSION: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.http://europepmc.org/articles/PMC4049638?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Georg Sebastian Nübling Johannes Levin Benedikt Bader Stefan Lorenzl Andreas Hillmer Tobias Högen Frits Kamp Armin Giese |
spellingShingle |
Georg Sebastian Nübling Johannes Levin Benedikt Bader Stefan Lorenzl Andreas Hillmer Tobias Högen Frits Kamp Armin Giese Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. PLoS ONE |
author_facet |
Georg Sebastian Nübling Johannes Levin Benedikt Bader Stefan Lorenzl Andreas Hillmer Tobias Högen Frits Kamp Armin Giese |
author_sort |
Georg Sebastian Nübling |
title |
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
title_short |
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
title_full |
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
title_fullStr |
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
title_full_unstemmed |
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
title_sort |
modelling ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
BACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. METHODS: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. RESULTS: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+) induced asyn129E oligomers and markedly reduced in Al(3+) induced oligomers. CONCLUSION: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase. |
url |
http://europepmc.org/articles/PMC4049638?pdf=render |
work_keys_str_mv |
AT georgsebastiannubling modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT johanneslevin modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT benediktbader modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT stefanlorenzl modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT andreashillmer modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT tobiashogen modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT fritskamp modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers AT armingiese modellingser129phosphorylationinhibitsmembranebindingofporeformingalphasynucleinoligomers |
_version_ |
1725262024128069632 |