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.
Biophys Chem. 2025 Mar;318:107379. doi: 10.1016/j.bpc.2024.107379. Epub 2024 Dec 13.
Parkinson's disease (PD) is a neurodegenerative disorder involving the progressive loss of dopaminergic neurons in the substantia nigra pars compacta triggered by the accumulation of amyloid aggregates of α-synuclein protein. This study investigates the potential of Salvianolic Acid B (SalB), a water-soluble polyphenol derived from Salvia miltiorrhiza Bunge, in modulating the aggregation of the A53T mutant of α-synuclein (A53T Syn). This mutation is associated with rapid aggregation and a higher rate of protofibril formation in early-onset familial PD. Computational and experimental approaches demonstrated Sal-B effectively prevents the amyloid fibrillation of A53T Syn by interacting with the N-terminal region and NAC domain. Sal-B particularly associates with the KTKEGV motif and NACore segment of A53T Syn by hydrophobic and hydrogen bonding interactions. Replica exchange molecular dynamics (REMD) simulations indicated that Sal-B reduces intramolecular hydrogen bonding and structural transitions into β-sheet rich conformations, thereby lowering the aggregation propensity of A53T Syn. Systematic analysis conducted using biophysical techniques and high-end microscopy has demonstrated significant inhibition in the amyloid transformation of A53T Syn corroborated by a 92 % decrease in ThT maxima at 100 μM Sal-B concentration and microscopic techniques validated the absence of mature fibrillar amyloids. DLS data revealed heterogeneous particle sizes, supporting the formation of smaller unstructured aggregates. These findings underscore Sal-B as a promising therapeutic candidate for PD and related synucleinopathies, warranting further investigation in cellular and animal models to advance potential treatments and early intervention strategies.
帕金森病（PD）是一种神经退行性疾病，由α-突触核蛋白的淀粉样聚集体积累引发，导致黑质致密部多巴胺能神经元逐渐丧失。本研究调查了丹酚酸B（SalB）——一种从丹参中提取的水溶性多酚——调节α-突触核蛋白A53T突变体（A53T Syn）聚集的潜力。这种突变与早发性家族性帕金森病中快速聚集和较高的原纤维形成率有关。计算和实验方法表明，Sal-B通过与N端区域和NAC结构域相互作用，有效阻止了A53T Syn的淀粉样纤维形成。Sal-B特别通过疏水和氢键相互作用与A53T Syn的KTKEGV基序和NACore片段结合。副本交换分子动力学（REMD）模拟表明，Sal-B减少了分子内氢键和向富含β-折叠构象的结构转变，从而降低了A53T Syn的聚集倾向。使用生物物理技术和高端显微镜进行的系统分析表明，在100μM Sal-B浓度下，ThT最大值降低了92%，证实了对A53T Syn淀粉样转变有显著抑制作用，显微镜技术验证了不存在成熟的纤维状淀粉样蛋白。动态光散射（DLS）数据显示颗粒大小不均一，支持形成较小的无结构聚集体。这些发现强调Sal-B是帕金森病和相关突触核蛋白病的一个有前景的治疗候选物，值得在细胞和动物模型中进一步研究，以推进潜在的治疗方法和早期干预策略。
