Amyloid fibril seeding and propagation of fibrils throughout the brain have been increasingly implicated in neurodegenerative progression in diseases such as Parkinson’s and Alzheimer’s. In the case of Parkinson’s disease (PD), our current understanding of the mechanism through which amyloid fibrils are able to act as templates to seed the misfolding of endogenous monomeric α-synuclein is limited. Fibril polymorphism is now thought to play a role in modulating the recruitment and induction of monomeric α-synuclein to aggregate, by providing different templating interfaces from different proto-filament packing. But is polymorphism the only modulator of seeding ability? By studying the interaction of α-synuclein with the neuroprotective intrinsically disordered protein β-synuclein using solid-state NMR, we have found that α-synuclein co-incubated fibrils formed with β-synuclein (co-αS/βS fibrils) have increased dynamics of residues in the N-terminally located KTKEGV imperfect repeats. Further solid-state NMR measurements of water accessibility also indicated that these residues are more water accessible in the co-αS/βS fibrils compared to the α-synuclein fibril. Further data shows that co-αS/βS fibrils are less toxic, are more resistant to shed monomers, and exhibit reduced capacity to seed aggregation in cell compared to α-synuclein fibrils alone. This work highlights a new dimension in our understanding of the mechanisms of fibril seeding and propagation in the cell, and suggests that the dynamics at the proto-fibril interface of the templating fibril can play an important role in these processes.

Amyloid fibril dynamics contribute to seeding properties of α-synuclein aggregation

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.