Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity

Abstract

Alpha-synuclein (S) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinsons disease and other synucleinopathies. {beta}-Synuclein ({beta}S), which co-localizes with S, has been shown to provide a neuroprotective effect, but the molecular mechanism by which this occurs remains elusive. Here we show that S fibrils formed in the presence of {beta}S are less cytotoxic, exhibit reduced cell seeding capacity and are more resistant to fibril shedding compared to S fibrils alone. Using solid-state NMR, we found that the overall structure of the core of S fibrils when co-incubated with {beta}S is minimally perturbed, however, the dynamics of Lys and Thr residues, located primarily in the imperfect KTKEGV repeats of the S N-terminus, are increased. Our results suggest that amyloid fibril dynamics may play a key role in modulating toxicity and seeding. Thus, enhancing the dynamics of amyloid fibrils may be a strategy for future therapeutic targeting of neurodegenerative diseases.