Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Madrid, Spain.
Centro de Biología Molecular Severo Ochoa, CSIC, Madrid, Spain.
J Alzheimers Dis. 2021;79(3):1143-1156. doi: 10.3233/JAD-201077.
Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer's disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent toxicity and progress of the disease.
We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio.
We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme.
The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases.
The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies.
Tau 是一种微管相关蛋白，可调节微管的稳定性和微管依赖性轴突运输。其过度磷酸化形式是阿尔茨海默病和其他 Tau 病的标志之一，也是形成这些神经退行性疾病中异常蛋白缠结的双螺旋丝的主要成分。人们普遍认为 Tau 的磷酸化程度是蛋白激酶和磷酸酶活性平衡的结果。这两种酶活性之间的平衡被破坏被认为是 Tau 过度磷酸化以及随后的毒性和疾病进展的根源。
我们探讨了这样一种可能性，即除了磷酸酶对磷酸化 Tau 的作用之外，PKA 的催化亚基还可以根据 ATP/ADP 比，催化 Tau 的磷酸化和去磷酸化。
我们使用不同磷酸化形式的 Tau 所经历的相对电泳迁移率的变化，作为酶催化作用的传感器。
结果与 PKA 和许多其他蛋白激酶催化的磷酸化反应（ATP+蛋白=ADP+磷酸化蛋白）的长期已知热力学可逆性一致。
这些结果有助于将神经元的分区化能量状态和线粒体功能障碍置于 Tau 相关病理学的上游。
