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EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers

Nature Structural & Molecular Biology volume 15, pages 558–566 (2008)Cite this article

Abstract

The accumulation of β-sheet–rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson's and Alzheimer's diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (−)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both α-synuclein and amyloid-β by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of β-sheet–rich amyloid, the formation of unstructured, nontoxic α-synuclein and amyloid-β oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.

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Figure 1: EGCG inhibits αS fibrillization.
Figure 2: EGCG binds to unfolded αS monomer.
Figure 3: Analysis of EGCG binding to αS with NMR.
Figure 4: EGCG inhibits β-sheet secondary-structure formation of αS.
Figure 5: EGCG-generated αS oligomers do not catalyze amyloid fibrillogenesis and are nontoxic in cell-based assays.
Figure 6: EGCG induces formation of nonamyloid spherical aggregates of Aβ42.
Figure 7: EGCG-stabilized Aβ42 aggregates are seeding incompetent and nontoxic structures.
Figure 8: Working models of effects of EGCG on αS fibrillogenesis.

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Acknowledgements

We thank S. Rautenberg, G. Grelle, S. Kostka, S. Plassmann and N. Schugardt for technical assistance, E. Müller and A. Otto for MS, J. Russ for kinetic experiments, S. Engelender for providing αS cDNA, S. Schnoegl for critical reading of the manuscript and editorial support, C. Haenig for computer support, and the department of M. Bienert, Leibnitz-Institute for Molecular Pharmacology, for the use of their CD spectrometer. A.P. and L.M. thank J. Christodoulou for the α-synuclein plasmid and for the spectral assignment in an electronic form. The project was funded by the NGFN2 program of the German Federal Ministry of Education and Research (BMBF, to E.E.W.), APOPIS (to E.E.W. and M.H.) and Deutsche Forschungsgemeinschaft (to D.E.E., E.E.W., A.B., M.H. and S.E.).

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  1. Dagmar E Ehrnhoefer and Jan Bieschke: These authors contributed equally to the work.

Authors and Affiliations

  1. Max Delbrueck Center for Molecular Medicine (MDC), AG Neuroproteomics, Robert-Roessle-Straße 10, Berlin, 13092, Germany

    Dagmar E Ehrnhoefer, Jan Bieschke, Annett Boeddrich, Martin Herbst, Sabine Engemann & Erich E Wanker

  2. National Institute for Medical Research (NIMR), The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Laura Masino & Annalisa Pastore

  3. Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, 14195, Germany

    Rudi Lurz

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Contributions

D.E.E. performed αS and Aβ experiments and edited the manuscript; J.B. performed αS and Aβ experiments and edited the manuscript; A.B. and M.H. performed Aβ experiments; L.M. performed NMR experiments; R.L. performed EM experiments; S.E. and A.P. edited the manuscript; E.E.W. designed the study and wrote the manuscript.

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Correspondence to Erich E Wanker.

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Ehrnhoefer, D., Bieschke, J., Boeddrich, A. et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15, 558–566 (2008). https://doi.org/10.1038/nsmb.1437

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