Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 15, Issue 6, Pages 558-566Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1437
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Funding
- Medical Research Council [MC_U117533887, MC_U117584256] Funding Source: Medline
- MRC [MC_U117584256, MC_U117533887] Funding Source: UKRI
- Medical Research Council [MC_U117533887, MC_U117584256] Funding Source: researchfish
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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.
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