Small Molecule Modulators of α-Synuclein Phase Separation.

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Parkinson's disease (PD) is a progressive neurodegenerative disorder impacting motor control due to impaired brain nerve cells.
• Alpha-synuclein (α-Syn) protein aggregation and fibrillation are central hallmarks of PD pathology.
• Liquid-liquid phase separation (LLPS) and droplet formation of α-Syn are increasingly recognized as critical in PD pathogenesis.

Purpose of the Study:

• To synthesize novel zwitterionic compounds as potential inhibitors of α-Syn aggregation.
• To investigate the effect of these compounds on α-Syn liquid-liquid phase separation (LLPS).
• To evaluate the compounds' ability to prevent the formation of α-Syn fibrillary aggregates.

Main Methods:

• Synthesis of novel zwitterionic compounds.
• In vitro assays to assess α-Syn liquid-liquid phase separation (LLPS).
• Analysis of α-Syn fibril formation in the presence of synthesized compounds.

Main Results:

• Successful synthesis of novel zwitterionic compounds.
• Demonstrated concentration-dependent inhibition of α-Syn LLPS by the synthesized compounds.
• Significant reduction in the formation of α-Syn fibrillary aggregates.

Conclusions:

• Novel zwitterionic compounds effectively inhibit α-Syn LLPS and subsequent fibril formation.
• These compounds represent a promising therapeutic strategy for Parkinson's disease.
• Targeting α-Syn aggregation via LLPS inhibition is a viable approach for PD treatment.