Berrocal María, Corbacho Isaac, Vázquez-Hernández María, Ávila Jesús, Sepúlveda M Rosario, Mata Ana M
Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Avda. de Elvas s/n, 06006 Badajoz, Spain.
Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, C/Nicolás Cabrera 1, 28049 Madrid, Spain.
Biochim Biophys Acta. 2015 Jul;1852(7):1465-76. doi: 10.1016/j.bbadis.2015.04.007. Epub 2015 Apr 16.
Ca2+-ATPases are plasma membrane and intracellular membrane transporters that use the energy of ATP hydrolysis to pump cytosolic Ca2+ out of the cell (PMCA) or into internal stores. These pumps are the main high-affinity Ca2+ systems involved in the maintenance of intracellular free Ca2+ at the properly low level in eukaryotic cells. The failure of neurons to keep optimal intracellular Ca2+ concentrations is a common feature of neurodegeneration by aging and aging-linked neuropathologies, such as Alzheimer's disease (AD). This disease is characterized by the accumulation of β-amyloid senile plaques and neurofibrillary tangles of tau, a protein that plays a key role in axonal transport. Here we show a novel inhibition of PMCA activity by tau which is concentration-dependent. The extent of inhibition significantly decreases with aging in mice and control human brain membranes, but inhibition profiles were similar in AD-affected brain membrane preparations, independently of age. No significant changes in PMCA expression and localization with aging or neuropathology were found. These results point out a link between Ca2+-transporters, aging and neurodegeneration mediated by tau protein.
Ca2+ -ATP酶是质膜和细胞内膜转运蛋白，利用ATP水解产生的能量将胞质Ca2+ 泵出细胞（质膜钙泵）或泵入内部储存库。这些泵是真核细胞中维持细胞内游离Ca2+ 处于适当低水平的主要高亲和力Ca2+ 系统。神经元无法维持最佳细胞内Ca2+ 浓度是衰老和与衰老相关的神经病理学（如阿尔茨海默病，AD）导致神经退行性变的共同特征。这种疾病的特征是β-淀粉样老年斑的积累和tau蛋白的神经原纤维缠结，tau蛋白在轴突运输中起关键作用。在此我们展示了tau对质膜钙泵活性的一种新的抑制作用，且这种抑制作用呈浓度依赖性。在小鼠和对照人脑膜中，抑制程度随衰老显著降低，但在受AD影响的脑膜制剂中，抑制情况相似，与年龄无关。未发现随着衰老或神经病理学改变质膜钙泵的表达和定位有显著变化。这些结果指出了Ca2+ 转运蛋白、衰老和由tau蛋白介导的神经退行性变之间的联系。
