Amyloid fibril seeding has been increasingly implicated in neurodegenerative disease progression, however the molecular mechanism is not well characterized. In the fibril seeding process of α-synuclein (αS), pre-formed oligomers and fibrils can act as templates for endogenous monomer resulting in further fibril formation and disease development. In this talk we present experimental methods, including NMR, that allow us to identify the αS binding interface between monomer and pre-formed fibrils, and monomer and stable oligomers. Based on these data and previous results in the lab we propose a molecular mechanism by which fibrils and oligomers of α-synuclein (αS), seed aggregation of the monomer protein. We propose a model in which the dynamic N- and C- terminal flanking regions of the αS fibril interact with the N-terminal 11 residues of the αS monomer and suggest that the monomer is recruited to the fibril via its disordered regions. While the structured fibril core is known to be critical to the assembly of amyloid fibrils, we highlight the importance of the N and C-terminal fibril disordered regions as potential targets against amyloid seeding.

Alpha-synuclein (αS) fibril seeding: visualizing the binding interface between the monomer -fibril complex of αS by NMR

ACS Spring Meeting 2021

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