EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.
The accumulation of beta-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 alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
Ehrnhoefer
Dagmar E
DE
Max Delbrueck Center for Molecular Medicine, AG Neuroproteomics, 13092 Berlin, Germany.
Bieschke
Jan
J
Boeddrich
Annett
A
Herbst
Martin
M
Masino
Laura
L
Lurz
Rudi
R
Engemann
Sabine
S
Pastore
Annalisa
A
Wanker
Erich E
EE
D000682:Amyloid / Q000737:chemistry / Q000187:drug effects*; D017772:Amyloid Neuropathies / Q000188:drug therapy / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry; D058225:Plaque, Amyloid / Q000737:chemistry / Q000187:drug effects*; D011485:Protein Binding; D051844:alpha-Synuclein / Q000737:chemistry
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D051844:alpha-Synuclein; C444321:amyloid beta-protein (1-34); D002392:Catechin; C045651:epigallocatechin gallate