Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by Lewy bodies, primarily amyloid aggregates of alpha-synuclein (α-Syn).
• Inhibiting α-Syn aggregation is a key therapeutic strategy for PD.

Purpose of the Study:

• To screen FDA-approved drugs for their ability to inhibit α-Syn fibrillation.
• To identify potential therapeutic agents for Parkinson's disease.

Main Methods:

• Screening of 2320 FDA-approved drugs.
• Dose-response studies to determine compound potency.
• Inhibition of α-Syn aggregation in Caenorhabditis elegans and SH-SY5Y neuronal cells.
• Biophysical studies including microscale thermophoresis and NMR to confirm drug-α-Syn binding.

Main Results:

• Three lead compounds, sulfamerazine, lathosterol, and tamoxifen, were identified that inhibit α-Syn fibrillation.
• Sulfamerazine and lathosterol demonstrated higher potency in inhibiting α-Syn aggregation compared to tamoxifen.
• Sulfamerazine significantly reduced α-Syn aggregation and toxicity in a C. elegans PD model and α-Syn aggregate accumulation in SH-SY5Y cells.
• Binding of sulfamerazine to α-Syn was confirmed via microscale thermophoresis and NMR, revealing sequestration into soluble dispersed assemblies.

Conclusions:

• Sulfamerazine, lathosterol, and tamoxifen inhibit α-Syn fibrillation.
• Sulfamerazine shows significant therapeutic potential for Parkinson's disease by reducing α-Syn aggregation and toxicity.
• Sulfamerazine and its derivatives warrant further investigation as potential Parkinson's disease therapeutics.