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Open Access Highly Accessed Research article

Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level

Georg Nübling12, Benedikt Bader12, Johannes Levin12, Jenna Hildebrandt1, Hans Kretzschmar1 and Armin Giese1*

Author Affiliations

1 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 23, 81377, Munich, Germany

2 Neurologische Klinik und Poliklinik, Klinikum der Universität München, Marchioninistr. 15, 81377, Munich, Germany

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Molecular Neurodegeneration 2012, 7:35  doi:10.1186/1750-1326-7-35

Published: 23 July 2012

Abstract

Background

Fibrillar amyloid-like deposits and co-deposits of tau and α-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and α-synuclein are not well understood.

Results

We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with α-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3β exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of α-synuclein in pre-formed tau oligomers.

Conclusions

Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration.

Keywords:
α-Synuclein, Metal ion, Oligomer, Phosphorylation, Tau, Iron, Aluminium, GSK-3 beta, Alzheimer’s disease; Parkinson’s disease