Peptides as modulators of α-synuclein aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Alpha-synuclein aggregation in dopaminergic neurons is a key pathological hallmark of Parkinson's disease.
• The hypothesis that toxic amyloid species share common physicochemical features suggests cross-reactivity of inhibitors.
• Investigating inhibitors of one amyloidogenic protein for efficacy against others is a promising therapeutic strategy.

Purpose of the Study:

• To investigate the cross-reactivity of alpha-synuclein aggregation inhibitors with alpha-synuclein.
• To evaluate the impact of specific amino acid substitutions (MePhe, Phe, Tic) on peptide-alpha-synuclein interactions.
• To explore the potential of peptidomimetics in modulating alpha-synuclein fibril formation.

Main Methods:

• Synthesis and testing of heptapeptide analogues derived from an Aβ-peptide aggregation inhibitor.
• Evaluation of peptide interactions with alpha-synuclein monomers.
• Analysis of the influence of MePhe topography on alpha-synuclein aggregation.

Main Results:

• Peptide analogues demonstrated good affinity for alpha-synuclein monomers.
• The tested peptides promoted the aggregation process of alpha-synuclein.
• Modifications at the MePhe residue influenced the interaction and aggregation dynamics.

Conclusions:

• Peptide analogues can interact with alpha-synuclein and promote its aggregation.
• This study provides a foundation for developing peptidomimetics targeting alpha-synuclein.
• The findings suggest a strategy to shift the equilibrium towards mature fibrils, potentially mitigating toxic oligomer formation.