Conformational Dynamics of Α-Synuclein in Presence of Bare and Surface Functionalized Znonps

Abstract

Parkinson’s disease is a progressive neurodegenerative disorder associated with aggregation of α-synuclein (αS), resulting in formation of plaques in neurons described as Lewy bodies. α-synuclein is a small, soluble, and intrinsically disordered protein that upon gaining amyloidogenic conformation forms rigid cross-β sheet structure with fibril-like morphology via cytotoxic oligomeric intermediates. In recent years, nanoparticles have gained momentum due to their nano-size and large surface to volume ratio. The binding of α-synuclein onto nanoparticle surface is likely to induce conformational rearrangements, thereby anticipated to impede them in folding pathways and affect overall bio-reactivity of nanoparticle. In this subject, our study explores the positive and negative interface interaction of zinc oxide nanoparticle (ZnONP) with α-synuclein, and its following impact on protein fibrillation kinetics and fibril mediated cytotoxicity. The interaction studies of -synuclein monomer and ZnONPs interface at higher concentration is indicative of multi-layered adsorption of α-synuclein or significant rearrangement in protein orientation that ensures tight packaging leading to inhibition of protein fibrillation. Further, TEM micrographs of ZnONP complexed α-synuclein shows mesh like pattern as compared to fibril like structure found in wild type α-synuclein. Impressively, α-synuclein complexed with ZnONP shows remarkably lowered cytotoxicity against the SH-SY-5Y and THP-1 cells in-vitro, as compared to aggregated α-synuclein. Henceforth, this study provides new insight on the therapeutic potential of ZnONP in combating pathologies related to α-synuclein aggregation.