Different effects of alpha-Synuclein mutants on lipid binding and aggregation detected by single molecule fluorescence spectroscopy and ThT fluorescence-based measurements
ACS Chem Neurosci. 2019 Jan 3
Viktoria C. Ruf
Georg S. Nübling
|Type of Publication:||Journal Article|
Six alpha-Synuclein point mutations are currently known to be associated with familial par-kinsonism: A30P, E46K, H50Q, G51D, A53E and A53T. We performed a comprehensive in vitro analysis to study the impact of all aSyn mutations on lipid binding and aggregation be-havior. Markedly reduced lipid binding of A30P, moderately attenuated binding of G51D and only very slightly reduced binding for the other mutants were observed. A30P was particularly prone to form metal ion induced oligomers, whereas A53T exhibited only weak tendencies to form oligomers. In turn, fibril formation occurred rapidly in H50Q, G51D and A53T, but only slowly in A30P, suggesting mutants prone to form oligomers tend to form fibrils to a lesser extent. This was supported by the observation that fibril formation of wild type aSyn, A30P and A53T was impaired in the presence of ferric iron. Additionally, we found the aggregation kinetics of mixtures of A30P or A53T and wt aSyn to be determined by the faster aggregating aSyn variant. Our results implicate differential mechanisms playing a role in aSyn pathology on the molecular level. This might contribute to a better understanding of Parkinson´s disease pathogenesis and provide potential links to develop prevention strategies and disease-modifying therapy.