Comparison of Kinetics, Toxicity, Oligomer Formation, and Membrane Binding Capacity of α-Synuclein Familial Mutations at the A53 Site, Including the Newly Discovered A53V Mutation

Biochemistry
Ganesh M MohiteSamir K Maji

Abstract

The involvement of α-synuclein (α-Syn) amyloid formation in Parkinson's disease (PD) pathogenesis is supported by the discovery of α-Syn gene (SNCA) mutations linked with familial PD, which are known to modulate the oligomerization and aggregation of α-Syn. Recently, the A53V mutation has been discovered, which leads to late-onset PD. In this study, we characterized for the first time the biophysical properties of A53V, including the aggregation propensities, toxicity of aggregated species, and membrane binding capability, along with those of all familial mutations at the A53 position. Our data suggest that the A53V mutation accelerates fibrillation of α-Syn without affecting the overall morphology or cytotoxicity of fibrils compared to those of the wild-type (WT) protein. The aggregation propensity for A53 mutants is found to decrease in the following order: A53T > A53V > WT > A53E. In addition, a time course aggregation study reveals that the A53V mutant promotes early oligomerization similar to the case for the A53T mutation. It promotes the largest amount of oligomer formation immediately after dissolution, which is cytotoxic. Although in the presence of membrane-mimicking environments, the A53V mutation showed an extent of...Continue Reading

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Citations

Sep 16, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mary XylakiEvangelia Emmanouilidou
Jun 30, 2021·NPJ Parkinson's Disease·Anthony R BraunJonathan N Sachs
Jul 3, 2021·International Journal of Molecular Sciences·Joanna A MotylRobert P Strosznajder
Aug 25, 2020·ACS Chemical Neuroscience·Karan SharmaSamir K Maji
Aug 31, 2021·Frontiers in Aging Neuroscience·Yi GuoHao Deng
Oct 12, 2021·Brain Communications·Nguyen-Vi MohamedThomas M Durcan

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