Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Alpha-synuclein (αSyn) aggregation into protein deposits is a key feature of neurodegenerative diseases, including Parkinson's disease (PD).
• Toxic αSyn species are implicated in cellular damage and disease progression.
• Inhibiting αSyn aggregation is a critical therapeutic target.

Purpose of the Study:

• To identify short peptides that inhibit αSyn aggregation and toxicity using a yeast model.
• To evaluate the efficacy of identified peptides in reducing αSyn-associated cellular damage and aggregation both in vitro and in vivo.

Main Methods:

• Utilized a budding yeast (S. cerevisiae) platform with a library of approximately one million peptide variants.
• Employed high-throughput screening to isolate peptides reducing αSyn toxicity and aggregation.
• Chemically synthesized lead peptides and assessed their inhibitory effects on αSyn aggregation in vitro and in human cells.

Main Results:

• Seven peptides were identified that specifically suppressed αSyn toxicity and aggregation in yeast cells.
• These peptides reduced reactive oxygen species and improved cell viability in yeast expressing αSyn.
• Two synthetic peptides, K84s and K102s, significantly inhibited αSyn oligomerization and aggregation in vitro at sub-stoichiometric concentrations.
• K84s demonstrated efficacy in reducing αSyn aggregation within human cells.

Conclusions:

• Identified novel peptide inhibitors (K84s and K102s) of alpha-synuclein aggregation.
• These peptides show therapeutic potential for Parkinson's disease and related disorders.
• Demonstrated the utility of yeast as a screening platform for discovering aggregation inhibitors.