The focus of the talk will be to gain therapeutic and mechanistic insights into the toxic states of Alpha-Synuclein (αS), a neuronal protein expressed at high levels in dopaminergic neurons in the brain. The aggregation of αS plays a major role in the formation of Lewy body inclusions, which is a pathological hallmark of Parkinson’s disease (PD). It has been suggested that the partitioning of αS between lipid membrane vesicles and the cellular milieu gets disturbed, which results in the formation of helical oligomers of αS in the cellular milieu and on membranes that eventually lead to αS fibrillation. A strong link has been established between PD and the formation of the helical multimerization. Therefore, strategies that prevent the formation of or disrupt these aberrant protein-protein interactions (PPIs), cytosol-based or membrane-bound helical multimers of αS, could lead to potential therapeutic interventions toward PD<b>. </b>However, there are many challenges in specifically targeting these aberrant PPIs: (1) There is very limited information about the chemical fingerprints of αS sequences that potentiate the formation of pathological αS multimerization. (2) Manipulation of the aberrant PPIs of αS with a small-molecule approach is often difficult owing to the non-covalent interactions spread over their large surface area.<br/>To address these challenges, we propose a synthetic protein mimetic based approach to target and manipulate the pathological helical αS multimers. The synthetic protein mimetics are organic scaffolds with a large surface area that imitate the topography and chemical fingerprints of an α-helix, such as those present at interfaces of PPIs. Using a variety of biophysical, in vitro, and in vivo assays, we have shown the modulation of synuclein multimerization and rescue of PD phenotypes. More importantly, using protein mimetics as chemical tools, we have identified chemical fingerprints of novel targets (αS subdomains) associated with αS aggregation.

Mechanistic investigation of various facets of synucleinopathies using synthetic protein mimetics

ACS Spring Meeting 2021

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