Rationally designed helical peptidomimetics disrupt α-synuclein fibrillation

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Misfolding of alpha-synuclein (α-Syn) leads to toxic fibrils and Lewy bodies, characteristic of Parkinson's disease.
• Understanding the structural basis of α-Syn misfolding is crucial for developing therapeutic interventions.

Purpose of the Study:

• To design and utilize peptidomimetics for selective recognition of native helical α-Syn.
• To investigate the potential of these peptidomimetics in inhibiting α-Syn aggregation and misfolding pathways.

Main Methods:

• Rational design of peptidomimetics targeting charged and hydrophobic residues on the helical α-Syn surface.
• Lipid-catalyzed aggregation assays using thioflavin-T.
• Electron microscopy to visualize aggregate structures.
• Circular dichroism spectroscopy for conformational analysis.

Main Results:

• Peptidomimetics demonstrated the ability to slow the rate of α-Syn aggregation under lipid-catalyzed conditions.
• Electron microscopy confirmed that the compounds disrupt the α-Syn misfolding pathway and aggregate formation.
• Control compounds and spectroscopic data supported the hypothesis of selective recognition.

Conclusions:

• A supramolecular approach using rationally designed peptidomimetics can effectively target and inhibit α-Syn misfolding.
• These compounds show potential as tools to study structure-function relationships in Parkinson's disease pathogenesis, including missense mutations and amyloid polymorphism.