On the Polymorph-Selection Determinants of α- Synuclein Amyloid Fibrils Studied at Atomic Resolution
Alpha-synuclein is an intensely studied intrinsically disordered protein whose aggregation into amyloid fibrils is connected to the progression of several neurodegenerative diseases, most commonly Parkinson’s Disease. A remarkable feature that has emerged from this research is how easy it is to induce the protein to aggregate in vitro into a wide range of amyloid fibrils that appear to resemble the aggregates found in Lewy bodies in diseases like Parkinson’s while at the same time how difficult it is to produce aggregates whose fold truly represents the disease-associated amyloids at the atomic level. In an effort to produce the disease-relevant fibrils in vitro we have analyzed over 60 independent samples by cryo-electron microscopy using helical reconstruction to obtain atomic resolution models for most of the samples. While not yet achieving our original goal, we have found that several overlooked parameters influence the structural outcomes of alpha-synuclein aggregation, in particular protein purity, preparation of the monomeric starting material and agitation method.