Phenolic compounds prevent the oligomerization of -synuclein and reduce synaptic toxicity

Lewy bodies, mainly composed of -synuclein (S), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited S fibrillation and destabilized preformed S fibrils. Cumulative evidence suggests that low-order S oligomers are neurotoxic and critical species in the pathogenesis of -synucleinopathies. To develop disease modifying therapies for -synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on S oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited S oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of S, whereas direct binding of RA to monomeric S was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated S synaptic toxicity by inhibition of S oligomerization. These results suggest that Myr and RA prevent the S aggregation process, reducing the neurotoxicity of S oligomers.