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bioRxiv · 10.1101/620401

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

Yang, X.·Williams, J.·Yan, R.·Mouradian, M. M.·Baum, J.
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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.

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Yang, X., Williams, J., Yan, R., Mouradian, M. M., Baum, J.. 2019-04-26. Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity. https://doi.org/10.1101/620401

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