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Inhibition of Prion Propagation by 3,4-Dimethoxycinnamic Acid
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Neurodegenerative diseases are associated with accumulation of amyloid-type protein misfolding products. Prion protein (PrP) is known for its ability to aggregate into soluble oligomers that in turn associate into amyloid fibrils. Preventing the formation of these infective and neurotoxic entities represents a viable strategy to control prion diseases. Numerous attempts to find dietary compounds with anti-prion properties have been made; however, the most promising agent found so far was curcumin, which is poorly soluble and merely bioavailable. In the present work, we identify 3,4-dimethoxycinnamic acid (DMCA) which is a bioavailable coffee component as a perspective anti-prion compound. 3,4-Dimethoxycinnamic acid was found to bind potently to prion protein with a Kd of 405 nM. An in vitro study of DMCA effect on PrP oligomerization and fibrillization was undertaken using isothermal titration calorimetry (ITC), dynamic light scattering (DLS) and circular dichroism (CD) methodologies. We demonstrated that DMCA affects PrP oligomer formation reducing the oligomer content by 30-40%, and enhancing SH-SY5Y cell viability treated with prion oligomers. Molecular docking studies allowed to suggest a site where DMCA is able to bind stabilizing PrP tertiary structure. We suggest that DMCA is a perspective dietary compound for prophylaxis of neurodegenerative diseases that needs further research.
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