Parishin C modulates the amyloid transformation of alpha-synuclein protein by apparently interacting with the NAC domain.

Parkinson's disease (PD) is a neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons in the brain and the presence of Lewy bodies (LB) within the remaining affected neurons, comprised of α-synuclein protein aggregates. Herein, we report a novel amyloid inhibitory potential of Parishin C on the amyloid transformation of the α-synuclein protein. Our studies involving computational screening and REMD simulation analysis revealed a strong interaction between Parishin C and the non-amyloid component (NAC domain), a known aggregation-prone region of the α-synuclein protein. Thioflavin T fluorescence assay demonstrated the inhibitory effect of Parishin C on amyloid transformation kinetics of α-synuclein, where even at the lowest concentration of Parishin C there was a 72 % reduction in the ThT maxima. ANS binding assay further revealed its ability to alter the surface hydrophobicity of the protein. An extensive evaluation using biophysical techniques indicated that Parishin C effectively prevented the formation of mature fibrillar species and promoted the formation of lower order aggregates with reduced cross-β-sheet signatures compared to the native α-synuclein aggregates. Collectively, our research highlights Parishin C's potential as a structural blueprint for developing new therapeutic compounds aimed at preventing the amyloidogenic transition in Parkinson's disease and related disorders.