Identification Of Two Novel Peptides That Inhibit Alpha-Synuclein Toxicity And Aggregation

Aggregation of alpha-synuclein (alpha Syn) into proteinaceous deposits is a pathological hallmark of a range of neurodegenerative diseases including Parkinson's disease (PD). Numerous lines of evidence indicate that the accumulation of toxic oligomeric and prefibrillar alpha Syn species may underpin the cellular toxicity and spread of pathology between cells. Therefore, aggregation of alpha Syn is considered a priority target for drug development, as aggregation inhibitors are expected to reduce alpha Syn toxicity and serve as therapeutic agents. Here, we used the budding yeast S. cerevisiae as a platform for the identification of short peptides that inhibit alpha Syn aggregation and toxicity. A library consisting of approximately one million peptide variants was utilized in two high-throughput screening approaches for isolation of library representatives that reduce alpha Syn-associated toxicity and aggregation. Seven peptides were isolated that were able to suppress specifically alpha Syn toxicity and aggregation in living cells. Expression of the peptides in yeast reduced the accumulation of alpha Syn-induced reactive oxygen species and increased cell viability. Next, the peptides were chemically synthesized and probed for their ability to modulate alpha Syn aggregation in vitro. Two synthetic peptides, K84s and K102s, of 25 and 19 amino acids, respectively, significantly inhibited alpha Syn oligomerization and aggregation at sub-stoichiometric molar ratios. Importantly, K84s reduced alpha Syn aggregation in human cells. These peptides represent promising alpha Syn aggregation antagonists for the development of future therapeutic interventions.