The Inhibition of α-Synuclein Aggregation by a Peptide Borrowed from Nature

Misfolding and aggregation of proteins is a major pathological feature in a variety of neurodegenerative diseases. Parkinson’s disease (PD) primarily results from a severe and selective damage of dopaminergic neurons, where insoluble and fibrillar α-Synuclein (αS) makes up the major component of inclusion bodies in these neurons. The inhibition of αS aggregation is considered as an efficient approach for preventing or treating PD. So far, several strategies have been applied on screening for the inhibitors that are able to suppress, slow down, or reverse αS aggregation, particularly at its early stages and a vast range of diverse molecules have been studied as potential inhibitors. An attractive therapeutic strategy is to block the early steps of misfolding and aggregation of the soluble protein by peptides. In this work, for finding a novel peptide inhibitor, a new database has been established by segmentation of all the proteins deposited in protein Data Bank. The database was searched for the sequences which adopt β structure and are identical or very similar to the regions of αS which are involved in aggregation. The adjacent β strands of the found sequences were chosen as the peptide inhibitors of αS aggregation. The predicted peptide was experimentally proved to be efficient in suppressing aggregation of αS by fluorescence spectroscopy and electron microscopy in vitro. The influence of the peptide inhibitor on cell toxicity of aggregation products of αS was investigated by MTT assay on human SH-SY5Y neuroblastoma cells and was shown that the peptide inhibitor greatly diminished the cell toxicity of the aggregation products of αS. Moreover, this peptide exhibited the ability to disrupt oligomers of αS which are assumed to be the pathogenic species in PD. Our findings suggest the therapeutic potential of this peptide for treatment of the rare inherited forms of PD