Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1454-1463. doi: 10.1016/j.bbadis.2017.02.002. Epub 2017 Feb 4.
Several retrospective epidemiological reports have indicated an inverse correlation between smoking and development of Parkinson's disease (PD). This has mostly been attributed to the neuroprotective role of nicotine in stimulating nicotinic acetylcholine receptors and dopaminergic neurons which are damaged in PD. One of the characteristic features of PD is the intraneuronal deposition of globular inclusions of the intrinsically disordered protein α-synuclein as Lewy bodies. Using in vitro and the well-validated yeast cell models, we show that nicotine also exerts a beneficial effect on aggregation of α-synuclein. The alkaloid increases the lag time of the nucleation step and reduces the build-up of the more toxic oligomeric species in a concentration-dependent manner. This results in lower oxidative stress in the cell, reduced cytotoxicity and increased cell survival. Structural studies using CD spectroscopy and fluorescence quenching showed that α-synuclein forms a transient complex with nicotine, distorting its native structure and altering its aggregation landscape such that the formation of oligomers is inhibited. As soluble oligomers are believed to modulate the mechanism of PD pathogenesis mainly by formation of pores in neuronal membranes, resulting in leaching of vital components of the cytoplasm with deleterious effects for the cell, our results provide a mechanistic rationale for the observed beneficial role of nicotine on the progression of the disease.
几项回顾性流行病学报告表明，吸烟与帕金森病（PD）的发展呈负相关。这主要归因于尼古丁刺激烟碱型乙酰胆碱受体和多巴胺能神经元的神经保护作用，而这些受体和神经元在 PD 中受到损伤。PD 的一个特征是α-突触核蛋白作为路易体的不溶性包涵体在神经元内沉积。我们使用体外和经过充分验证的酵母细胞模型表明，尼古丁对α-突触核蛋白的聚集也有有益的影响。这种生物碱以浓度依赖的方式增加成核步骤的滞后时间，并减少更具毒性的寡聚物的积累。这导致细胞内的氧化应激降低，细胞毒性降低，细胞存活率增加。使用 CD 光谱和荧光猝灭的结构研究表明，α-突触核蛋白与尼古丁形成瞬态复合物，扭曲其天然结构并改变其聚集景观，从而抑制寡聚物的形成。由于可溶性寡聚物被认为主要通过在神经元膜中形成孔来调节 PD 发病机制，导致细胞质中的重要成分流失，对细胞产生有害影响，因此我们的结果为观察到的尼古丁对疾病进展的有益作用提供了一种机制上的解释。
