Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and the abnormal accumulation of alpha-synuclein (α-syn) aggregates or Lewy bodies in the substantial nigra of the brain. Apart from this accumulation, PD is also characterized by a loss of motor function, tremor, rigidity, and postural instability. α-Syn is an intrinsically disordered protein involved in vesicular trafficking and neurotransmitter release. The aggregation of α-syn involves a cascade of structural transition from a monomeric protein to the fibrillar form of protein, a complex process regulated by several intrinsic and extrinsic factors. Nanoparticles have been reported for easy drug delivery as they can easily cross the blood–brain barrier. Several reports suggest that the interface of metal oxide nanoparticles directly affects α-syn conformation and can positively inhibit amyloidogenesis. Some reports also indicated that metal ion-catalyzed oxidation (MCO) of α-syn favors the formation of dityrosine linkage, which forms soluble aggregates rather than insoluble fibrils. However, the mechanism behind the dityrosine-mediated α-syn aggregation is unclear. Therefore, in this report, our study primarily focuses on the potential use of metal nanoparticles to induce a dityrosine-mediated inhibition of α-syn fibrillation. Using a combination of biophysical methods, we have found that ZnONP with a negative interface has more affinity for monomeric α-syn, strongly inhibits the fibrillation kinetics of α-syn in a dose-dependent manner resulting in the flocculation of the resultant complex, which is a kinetically favorable process. α-Syn interacted with ZnONPs via multi-layered adsorption and led to the formation of amorphous aggregates known as flocs (flocculation) instead of fibrillar structures. Interestingly, we found that oxidative stress exerted by ZnONP induced the formation of dityrosine cross-linkage in α-syn. In conclusion, this intramolecular cross-linking favors the flocculation process to form a compact yet disordered α-syn monomer instead of an ordered amyloid fibril.
Author Contributions
Conceptualization, methodology, validation, formal analysis, writing—original draft preparation are done by S.J. (Sonali Jena); Conceptualization, methodology, writing—review and editing, supervision, project administration, and funding acquisition are done by S.J. (Suman Jha). All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by Indian Council of Medical Research [grant number: 35/05/2020-Nano/BMS], Govt. of India and Department of Science and Technology [grant number: ST-BT-MISC-0020-2018-4002/ST], Govt. of Odisha, India.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data are available on request upon the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
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