Research Progress of α-Synuclein Aggregation Inhibitors for Potential Parkinson's Disease Treatment

Abstract

Introduction: Parkinson's disease (PD) is characterized by fibrillation of disordered proteins known as Lewy bodies in the substantia nigra that also undergo progressive neurodegeneration. The aggregation of α-synuclein (α-syn) is a hallmark and potentially a critical step in the development of Parkinson's disease and other synucleinopathies. The synaptic vesicle protein α-syn is a small, abundant, highly conserved disordered protein and the causative agent of neurodegenerative diseases. Several novel pharmacologically active compounds are used to treat PD and other neurodegenerative disorders. Though, the mechanism through which these molecules inhibit the α-syn aggregation is still not fully understood.

Objective: This review article is focused on the recent advancements in compounds that can inhibit the development of α-syn fibrillation and oligomerization.

Methods: The current review article is based on the most recent and frequently cited papers from Google Scholar, SciFinder, and Researchgate sources.

Description: In the progression of PD, the mechanism of α-syn aggregation involves the structural transformation from monomers into amyloid fibrils. As the accumulation of α-syn in the brain has been linked to many disorders, the recent search for disease-modifying medications mainly focused on modifying the α-syn aggregation. This review contains a detailed report of literature findings and illustrates the unique structural features, structure-activity relationship, and therapeutic potential of the natural flavonoids in the inhibition of α-syn are also discussed.

Conclusion: Recently, many naturally occurring molecules such as curcumin, polyphenols, nicotine, EGCG, and stilbene have been recognized to inhibit the fibrillation and toxicity of α-syn. Therefore, knowing the α-synuclein filament's structure and how they originate will help invent particular biomarkers for synucleinopathies and develop reliable and effective mechanism-based therapeutics. We hope the information this review provides may help evaluate novel chemical compounds, such as α- syn aggregation inhibitors, and will contribute to developing novel drugs for treating Parkinson's disease.

Keywords: Inhibitors; Intrinsically disordered protein; Parkinson’s disease; Presynaptic; Structure-activity relationship; α-Synuclein aggregation.