Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.
Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.
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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 anodized pearl price xbox 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 caruso rhodiola 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.