The Library Derived 4554W Peptide Inhibits Primary Nucleation of α-Synuclein

Aggregation of alpha-Synuclein (aS) is widely regarded as a key factor in neuronal cell death, leading to a wide range of synucleinopathies that includes Parkinson’s Disease. Development of therapeutics has therefore focused on inhibiting aggregation of aS into toxic forms. One such inhibitor, based on the preNAC region aS45-54 (4554W), was identified using an intracellular peptide library screen, and subsequently shown to both inhibit formation of aS aggregates while simultaneously lowering toxicity. Subsequent efforts have sought to determine the mode of 4554W action. In particular, and consistent with the fact that both target and peptide are co-produced during library screening, we find that the peptide inhibits primary nucleation of aS, but does not modulate downstream secondary nucleation or elongation events. These findings hold significant promise towards mechanistic understanding and development of molecules that can module the first steps in aS aggregation towards novel treatments for Parkinson’s disease and related synucleinopathies.