Stepanov Alexander, Karelina Tatiana, Markevich Nikolai, Demin Oleg, Nicholas Timothy
InSysBio, Moscow, Russia.
Pfizer Global R&D, Groton, Connecticut, United States of America.
PLoS One. 2018 Feb 6;13(2):e0192519. doi: 10.1371/journal.pone.0192519. eCollection 2018.
Abnormal tau metabolism followed by formation of tau deposits causes a number of neurodegenerative diseases called tauopathies including Alzheimer's disease. Hyperphosphorylation of tau protein precedes tau aggregation and is a topic of interest for the development of pharmacological interventions to prevent pathology progression at early stages. The development of a mathematical model of multisite phosphorylation of tau would be helpful for searching for the targets of pharmacological interventions and candidates for biomarkers of pathology progression. In the present study, we for the first time developed a model of multisite phosphorylation of tau protein and elucidated the relative contribution of kinases to phosphorylation of distinct sites. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3β and CDK5 and dephosphorylation by PP2A, accurately reproducing the data for short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may more specifically prevent tau hyperphosphorylation, e.g., on PHF sites, which are key biomarkers of pathological changes in Alzheimer's disease. The main features of our model are partial phosphorylation of tau residues and merging of random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events.
异常的tau蛋白代谢随后形成tau沉积物会导致多种被称为tau蛋白病的神经退行性疾病，包括阿尔茨海默病。tau蛋白的过度磷酸化先于tau蛋白聚集，并且是开发用于预防早期病理进展的药理学干预措施的一个研究热点。开发tau蛋白多位点磷酸化的数学模型将有助于寻找药理学干预的靶点以及病理进展生物标志物的候选物。在本研究中，我们首次开发了tau蛋白多位点磷酸化模型，并阐明了激酶对不同位点磷酸化的相对贡献。该模型描述了GSK3β和CDK5对tau蛋白或PKA预磷酸化的tau蛋白的磷酸化以及PP2A的去磷酸化，准确地再现了tau蛋白（去）磷酸化的短期动力学数据。我们的结果表明，激酶抑制可能更特异性地预防tau蛋白过度磷酸化，例如在PHF位点上，这些位点是阿尔茨海默病病理变化的关键生物标志物。我们模型的主要特征是tau蛋白残基的部分磷酸化以及在基于概率的方法框架内假设独立磷酸化事件的多位点磷酸化的随机和顺序机制的合并。
