Increased Dynamics of ?-Synuclein Fibrils by ?-Synuclein Leads to Reduced Seeding and Cytotoxicity.

ABSTRACT: Alpha-synuclein (?S) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies. ?-Synuclein (?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 ?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 ?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.

SUBMITTER: Yang X 

PROVIDER: S-EPMC6879756 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature