Engineered α-synuclein prevents wild type and familial Parkin variant fibril formation

Abstract

α-Synuclein is a major component of several pathological lesions diagnostic of specific neurodegenerative disease such as Parkinson’s disease. This study focuses on the non-amyloid β component of Alzheimer’s disease amyloid, a key region for the aggregation and fibril formation of α-synuclein. Several mutations were introduced in an attempt to repress β-strand formation and hydrophobic interaction-based aggregation. Although reducing the hydrophobicity drastically decreased fibril formation, the Val70Thr and Val70Pro mutations resulted in an unstable secondary structure thereby increasing non-structural aggregation, instead of fibril formation. Therefore, the stabilization of non-structural natively unfolded status is important to prevent α-synuclein fibril formation. Mixing the Val70Thr/Val71Thr double mutant, which has inherently low potential, with the fibril forming α-synucleins, WT and Ala53Thr, greatly reduced their fibril formation and aggregation. This double mutant has great potential for further therapeutic approaches.