Session Information
Date: Tuesday, June 21, 2016
Session Title: Pathophysiology (other movement disorders)
Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To dissect the complex interplay of tau hyperphosphorylation, metal ion induced oligomer formation and membrane interactions applying single particle fluorescence techniques.
Background: Fibrillar deposits of protein tau are a key hallmark of several neurodegenerative diseases. A mounting body of evidence points towards a complex interplay of different factors such as phosphorylation and metal ions in the formation of small tau oligomers. These oligomers are likely to be a key neurotoxic aggregate species in tauopathies. Furthermore, tau-membrane interactions have recently come into focus as a potential mode of action of tau toxicity.
Methods: We investigated interactions of human recombinant tau and alpha-synuclein (asyn) monomers and Fe3+/Al3+-induced oligomers with small unilamellar vesicles (SUV) derived from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and dipalmitoylphosphatidylcholine (DPPC) as well as the influence of GSK-3β-mediated tau phosphorylation. Applying single-particle fluorescence techniques, protein-membrane interactions were observed at nanomolar protein concentrations at the single particle level.
Results: Tau monomers show no binding to neutral lipid surfaces irrespective of their phosphorylation state, whereas asyn binding depends on surface configuration. Asyn monomer was observed only to bind to gel-state membranes. In contrast, metal ion induced tau oligomers show a gain of function in binding to neutral lipid surfaces, reminiscent of effects described for asyn earlier. Of note, tau phosphorylation by GSK-3β increases both oligomer formation and membrane affinity of the resulting oligomers.
Conclusions: Our data imply a potential synergistic role of metal-ion induced tau oligomer formation and tau hyperphosphorylation in fostering protein-membrane interactions. Similar effects seen in metal ion induced asyn oligomers point towards a common pathological mechanism of tauopathies and synucleinopathies. The high binding affinity of these oligomers may result in membrane disruption, or may pose a potential means of transcellular transfer of tau pathology.
To cite this abstract in AMA style:
G.S. Nuebling, E. Plesch, T. Högen, S. Lorenzl, F. Kamp, A. Giese. Phosphorylation by GSK-3β enhances binding of metal ion induced tau oligomers to neutral lipid surfaces [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/phosphorylation-by-gsk-3-enhances-binding-of-metal-ion-induced-tau-oligomers-to-neutral-lipid-surfaces/. Accessed June 15, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/phosphorylation-by-gsk-3-enhances-binding-of-metal-ion-induced-tau-oligomers-to-neutral-lipid-surfaces/