Interaction with zinc oxide nanoparticle kinetically traps α-synuclein fibrillation into off-pathway non-toxic intermediates.

α-Synuclein is an intrinsically disordered amyloidogenic protein associated with Parkinson's disease (PD). The monomeric α-synuclein transition into amyloid fibril involves multiple steps, which are affected by several intrinsic and extrinsic factors. This increases complexities in development of targeted therapeutics against the pathological intermediate(s). Several studies have been dedicated to find an effective molecule to inhibit the detrimental amyloidogenesis. In recent years, metal oxide nanoparticle interfaces have shown direct effects on protein conformation, hence may be adopted as an alternative potential therapeutic approach against amyloidosis. In this context, our study explores the zinc oxide nanoparticle (ZnONP) with negative surface potential interface interaction with α-synuclein, and subsequent impact of the interaction on the protein fibrillation and the fibril-mediated cytotoxicity. N-terminus amphipathic "KA/TKE/QGV" repeating motifs in α-synuclein primarily interact with the ZnONP interface that enthalpically drives initial adsorption of the protein onto the interface. Whereas, subsequent bulk-protein adsorption onto the hard-corona is entropically driven, leading into flocculation of the complex. The flocs appear as amorphous mesh-like morphology in TEM micrographs, as opposed to the typical fibrils formed by the wild-type protein. Interestingly, α-synuclein in complex with ZnONP shows significantly lowered cytotoxicity against the IMR32 and THP-1 cells in-vitro, as compared to fresh α-synuclein.