Navigating α‐Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets

Abstract

AbstractParkinson's disease is a yet incurable, age‐related neurodegenerative disorder characterized by the aggregation of small neuronal protein α‐synuclein into amyloid fibrils. Inhibition of this process is a prospective strategy for developing a disease‐modifying treatment. We overview here small molecule, peptide, and protein inhibitors of α‐synuclein fibrillization reported to date. Special attention was paid to the specificity of inhibitors and critical analysis of their action mechanisms. Namely, the importance of oxidation of polyphenols and cross‐linking of α‐synuclein into inhibitory dimers was highlighted. We also compared strategies of targeting monomeric, oligomeric, and fibrillar α‐synuclein species, thoroughly discussed the strong and weak sides of different approaches to testing the inhibitors.