Akhtar Almas, Singh Payal, Admane Nikita, Grover Abhinav
School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Biochim Biophys Acta Proteins Proteom. 2025 Jul 1;1873(4):141076. doi: 10.1016/j.bbapap.2025.141076. Epub 2025 May 7.
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.
帕金森病（PD）是一种神经退行性疾病，其特征是大脑中多巴胺能神经元逐渐退化，以及在剩余受影响神经元中存在路易小体（LB），路易小体由α-突触核蛋白聚集体组成。在此，我们报告了帕里辛C对α-突触核蛋白淀粉样变转化的一种新型淀粉样蛋白抑制潜力。我们涉及计算筛选和REMD模拟分析的研究表明，帕里辛C与非淀粉样成分（NAC结构域）之间存在强烈相互作用，NAC结构域是α-突触核蛋白中一个已知的易于聚集的区域。硫黄素T荧光测定法证明了帕里辛C对α-突触核蛋白淀粉样变转化动力学的抑制作用，即使在帕里辛C最低浓度下，硫黄素T最大值也降低了72%。ANS结合测定进一步揭示了其改变蛋白质表面疏水性的能力。使用生物物理技术进行的广泛评估表明，与天然α-突触核蛋白聚集体相比，帕里辛C有效地阻止了成熟纤维状物种的形成，并促进了具有减少的交叉β-折叠特征的低阶聚集体的形成。总的来说，我们的研究突出了帕里辛C作为开发旨在预防帕金森病及相关疾病中淀粉样变转变的新治疗化合物的结构蓝图的潜力。
