Aggregation of alpha synuclein (αS) into amyloid fibrils is associated with multiple neurodegenerative diseases, such as Parkinson’s Disease and Dementia with Lewy bodies. αS amyloid fibrils have been demonstrated to be toxic in cell, mouse, and monkey models. Thus suppression of αS amyloid formation is one approach to combat progression of these neurodegenerative diseases. However, once αS amyloidogenesis has commenced, fragmentation, seeding, and propagation of further fibril formation makes inhibition of the amyloid stage a complicated challenge. Here, we have purified two types of αS oligomers that do not convert into amyloid fibrils, and are not toxic to SH-SY5Y neuronal cells. These oligomers can be separated by size exclusion chromatography and have distinctive morphologies as seen by negative stain transmission electron microscopy. Moreover, through thioflavin T (ThT) fluorescence studies, we find that these non-propagating, non-toxic αS oligomers reduce αS fibril formation in a dose-dependent manner even in the presence of fibril seeds. The inhibitory properties of these oligomers thus make them an attractive target against αS amyloidogenesis. We use solution nuclear magnetic resonance spectroscopy methods in order to derive molecular details of oligomer interactions with αS monomers that may contribute to their fibril interference mechanism. Our results suggest that these auto-inhibitory oligomers interact with both αS fibril and monomer species, competing with fibril–monomer interactions, and reducing amyloid proliferation. Taken together, our results provide molecular insight into a possible mechanism of inhibition of pathological αS amyloidogenesis that is driven by an amyloid-incompetent species of αS.<br/><br/>

Auto-inhibitory interactions of alpha-synuclein reduce amyloid fibril seeding

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.