Foldamers reveal and validate therapeutic targets associated with toxic alpha-synuclein self-assembly

Inhibiting alpha-synuclein self-assembly into amyloid structures, associated with Parkinson's disease, is a potential therapeutic intervention. Here, the authors identify the domains/sequences that are essential for alpha-synuclein aggregation and test the activity of foldamer-based antagonists to identify potential therapeutic targets. Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (alpha S) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of alpha S aggregation. However, the bottleneck towards achieving this goal is the identification of alpha S domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified alpha S sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate alpha S sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of alpha S aggregation, which will pave the way for effective treatments for PD.