Sahoo Tarini Ashish, Chand Jagdish, Kandy Amarjith Thiyyar, Antony Shanish, Subramanian Gomathy
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, 643001, India.
Department of Pharmaceutical Sciences, Government Medical College, Kottayam, Kerala, 686008, India.
Neurochem Res. 2025 Apr 16;50(3):145. doi: 10.1007/s11064-025-04399-7.
Parkinson's disease is a complex neurological ailment manifested by dopaminergic neurodegeneration in the substantia nigra of the brain. This study investigates the molecular tripartite interaction between Lewy bodies, amyloid beta, and tau protein in the pathogenesis of Parkinson's disease. Lewy bodies which have been found as the important pathological hallmark in the degenerative neurons of Parkinson's patients, are mainly composed of α-synuclein. The accumulation of α-synuclein has been directly and indirectly linked to the severity and degree of progression of the disease. In addition, approximately 50% of Parkinson's disease cases are also described by hyperphosphorylation of tau protein indicating its significant involvement in the disease. The study further explains how α-synuclein, tau and amyloid beta can spread via cross-seeding mechanisms and accelerate each other's aggregation leading to neuronal death. Both GSK-3β and CDK5 are involved in phosphorylation which among other effects contributes to the misfolding of both α-synuclein and tau proteins that lead to neurodegeneration in Alzheimer's disease. Several mediators, that contribute to mitochondrial damage through elevated oxidative stress pathology are clearly described. Because of the increase in the incidence of Parkinson's disease, as predicted to be 17 million when the study was being conducted, studying these pathological mechanisms is very important in trying to establish treatments. This work contributes a path to finding a multi-target treatment regimen to alleviate the burden of this devastating disease.
帕金森病是一种复杂的神经疾病，表现为大脑黑质中的多巴胺能神经变性。本研究调查了路易小体、β淀粉样蛋白和tau蛋白在帕金森病发病机制中的分子三方相互作用。路易小体已被发现是帕金森病患者退化神经元中的重要病理标志，主要由α-突触核蛋白组成。α-突触核蛋白的积累与疾病的严重程度和进展程度直接或间接相关。此外，约50%的帕金森病病例还表现为tau蛋白的过度磷酸化，表明其在该疾病中具有重要作用。该研究进一步解释了α-突触核蛋白、tau蛋白和β淀粉样蛋白如何通过交叉播种机制传播，并加速彼此的聚集，导致神经元死亡。糖原合酶激酶-3β（GSK-3β）和细胞周期蛋白依赖性激酶5（CDK5）都参与磷酸化过程，这在其他作用中导致了α-突触核蛋白和tau蛋白的错误折叠，进而导致阿尔茨海默病中的神经变性。文中清楚地描述了几种通过氧化应激病理升高导致线粒体损伤的介质。由于帕金森病的发病率预计在开展该研究时将达到1700万，研究这些病理机制对于尝试建立治疗方法非常重要。这项工作为找到一种多靶点治疗方案以减轻这种毁灭性疾病的负担提供了一条途径。
