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

Abstract

Parkinson'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.

Chemistry in Ukraine

“…The current status of a Parkinson's disease treatment by using inhibitors of α-synuclein fibrillization process is reviewed by Galkin, Shvadchak, and co-workers. [20] Special attention is paid to the specificity of inhibitors and critical analysis of their action mechanisms. The authors also compare strategies of targeting monomeric, oligomeric, and fibrillar α-synuclein species, thoroughly discussing the strong and weak sides of different approaches to testing the inhibitors.…”

A Plant Model of α-Synucleinopathy: Expression of α-Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism

“…A promising avenue involves the identification of small molecules with anti-αSyn aggregation or stress-alleviating properties. Currently, a number of small-molecule inhibitors of αSyn aggregation from synthetic sources have been discovered, mostly through high-throughput screening strategies (e.g., [24][25][26]). However, plants offer another screening palette for the identification of aggregation inhibitors, expanding the potential pool of compounds that may hold therapeutic promise.…”

The 75–99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation

“…Heat shock proteins (HSPs) and proteins from endoplasmic reticulum play an important role in maintaining cellular protein homeostasis and can protect neurons from damage by degradation of aggregates through different mechanisms [10,11]. Therefore, in the search for new therapeutic strategies, α-synuclein aggregation and misfolding are considered a priority target for drug development [12][13][14].…”