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J Biol Chem. 2014 Aug 1;289(31):21299-310. doi: 10.1074/jbc.M114.554667. Epub 2014 Jun 6.

How epigallocatechin gallate can inhibit α-synuclein oligomer toxicity in vitro.

Author information

1
From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures.
2
From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Departments of Chemistry.
3
Biomedicine-Medical Biochemistry, and.
4
From the Interdisciplinary Nanoscience Center, Departments of Chemistry.
5
Biomedicine-Medical Immunology, Aarhus University, 8000 Aarhus C, Denmark.
6
From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, dao@inano.au.dk.

Abstract

Oligomeric species of various proteins are linked to the pathogenesis of different neurodegenerative disorders. Consequently, there is intense focus on the discovery of novel inhibitors, e.g. small molecules and antibodies, to inhibit the formation and block the toxicity of oligomers. In Parkinson disease, the protein α-synuclein (αSN) forms cytotoxic oligomers. The flavonoid epigallocatechin gallate (EGCG) has previously been shown to redirect the aggregation of αSN monomers and remodel αSN amyloid fibrils into disordered oligomers. Here, we dissect EGCG's mechanism of action. EGCG inhibits the ability of preformed oligomers to permeabilize vesicles and induce cytotoxicity in a rat brain cell line. However, EGCG does not affect oligomer size distribution or secondary structure. Rather, EGCG immobilizes the C-terminal region and moderately reduces the degree of binding of oligomers to membranes. We interpret our data to mean that the oligomer acts by destabilizing the membrane rather than by direct pore formation. This suggests that reduction (but not complete abolition) of the membrane affinity of the oligomer is sufficient to prevent cytotoxicity.

KEYWORDS:

Dynamic Light Scattering; EGCG; Isothermal Titration Calorimetry (ITC); Membrane; Nuclear Magnetic Resonance (NMR); Oligomer; Toxicity; X-ray Scattering; α-Synuclein

PMID:
24907278
PMCID:
PMC4118093
DOI:
10.1074/jbc.M114.554667
[Indexed for MEDLINE]
Free PMC Article

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