Inhibition of Phosphorylated Alpha-Synuclein Aggregation by Synthetic Protein Mimetics and Foldamers

The formation of Lewy bodies (LB) is a pathological hallmark for synucleinopathies, which is an umbrella term for many diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. One of the main components of LB is the aggregates of phosphorylated modification of α-Synuclein at residue 129 (αS-129), a neuronal protein expressed in the dopaminergic neurons in the brain. There are equivocal results about the role of αS-129, suggesting its involvement in both potentiating pathology and a functional role to rescue pathology. Regardless, a potential therapeutic strategy for LB-based pathologies could be the identification of inhibitors of both αS and αS-129 aggregation. However, to the best of our knowledge, there are no reports of ligands that can potently inhibit the aggregation of αS-129. Our group has recently identified potent antagonists of αS aggregation based on the oligopyridylamide (synthetic protein mimetics) and oligoquinoline (foldamers) scaffolds. Both ligands were potent antagonists of αS aggregation-mediated disease phenotypes in various PD models. Here, we tested both ligands against αS-129 aggregation and the coaggregation of αS and αS-129 (αS/αS-129). Both ligands were potent antagonists of αS-129 aggregation and coaggregation of αS/αS-129 in biophysical and cellular models of PD. Both ligands rescued cell toxicity mediated by the coaggregation of αS/αS-129. To the best of our knowledge, these are the first ligands that potently inhibit the major component of LB. This finding will aid in the development of therapeutic insights into aggregation-related synucleinopathies.