Inhibition\nof Phosphorylated Alpha-Synuclein Aggregation\nby Synthetic Protein Mimetics and Foldamers

The formation of Lewy bodies (LB) is a pathological hallmark\nfor\nsynucleinopathies, which is an umbrella term for many diseases, including\nParkinson’s disease, Lewy body dementia, and multiple system\natrophy. One of the main components of LB is the aggregates of phosphorylated\nmodification of α-Synuclein at residue 129 (αS-129), a\nneuronal protein expressed in the dopaminergic neurons in the brain.\nThere are equivocal results about the role of αS-129, suggesting\nits involvement in both potentiating pathology and a functional role\nto rescue pathology. Regardless, a potential therapeutic strategy\nfor LB-based pathologies could be the identification of inhibitors\nof both αS and αS-129 aggregation. However, to the best\nof our knowledge, there are no reports of ligands that can potently\ninhibit the aggregation of αS-129. Our group has recently identified\npotent antagonists of αS aggregation based on the oligopyridylamide\n(synthetic protein mimetics) and oligoquinoline (foldamers) scaffolds.\nBoth ligands were potent antagonists of αS aggregation-mediated\ndisease phenotypes in various PD models. Here, we tested both ligands\nagainst αS-129 aggregation and the coaggregation of αS\nand αS-129 (αS/αS-129). Both ligands were potent\nantagonists of αS-129 aggregation and coaggregation of αS/αS-129\nin biophysical and cellular models of PD. Both ligands rescued cell\ntoxicity mediated by the coaggregation of αS/αS-129. To\nthe best of our knowledge, these are the first ligands that potently\ninhibit the major component of LB. This finding will aid in the development\nof therapeutic insights into aggregation-related synucleinopathies.