alpha-synuclein and Amyloid-Neuropathies

Protein misfolding and formation of beta-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer's and Parkinson's disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and amyloid-beta fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature alpha-synuclein and amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to beta-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.

Topics: alpha-Synuclein; Amyloid; Amyloid beta-Peptides; Amyloid Neuropathies; Animals; Blotting, Western; Catechin; CHO Cells; Chromatography, Affinity; Circular Dichroism; Cricetinae; Cricetulus; Escherichia coli; Humans; Microscopy, Atomic Force; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Neuroprotective Agents; PC12 Cells; Rats

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.

Topics: alpha-Synuclein; Amyloid; Amyloid beta-Peptides; Amyloid Neuropathies; Catechin; Humans; Peptide Fragments; Plaque, Amyloid; Protein Binding

Topics: alpha-Synuclein; Amyloid beta-Peptides; Amyloid Neuropathies; Catechin; Humans; Peptide Fragments; Plaque, Amyloid