Department of Neuroscience, King's College London, Institute of Psychiatry, London, UK.
Neurobiol Aging. 2013 Sep;34(9):2146-57. doi: 10.1016/j.neurobiolaging.2013.03.015. Epub 2013 Apr 17.
Phosphorylated forms of microtubule-associated protein tau accumulate in neurofibrillary tangles in Alzheimer's disease. To investigate the effects of specific phosphorylated tau residues on its function, wild type or phosphomutant tau was expressed in cells. Elevated tau phosphorylation decreased its microtubule binding and bundling, and increased the number of motile tau particles, without affecting axonal transport kinetics. In contrast, reducing tau phosphorylation enhanced the amount of tau bound to microtubules and inhibited axonal transport of tau. To determine whether differential tau clearance is responsible for the increase in phosphomimic tau, we inhibited autophagy in neurons which resulted in a 3-fold accumulation of phosphomimic tau compared with wild type tau, and endogenous tau was unaffected. In autophagy-deficient mouse embryonic fibroblasts, but not in neurons, proteasomal degradation of phosphomutant tau was also reduced compared with wild type tau. Therefore, autophagic and proteasomal pathways are involved in tau degradation, with autophagy appearing to be the primary route for clearing phosphorylated tau in neurons. Defective autophagy might contribute to the accumulaton of tau in neurodegenerative diseases.
磷酸化的微管相关蛋白 tau 聚集在阿尔茨海默病的神经纤维缠结中。为了研究特定磷酸化 tau 残基对其功能的影响，在细胞中表达了野生型或磷酸突变型 tau。tau 的磷酸化升高降低了其微管结合和捆绑能力，并增加了运动性 tau 颗粒的数量，而不影响轴突运输动力学。相比之下，降低 tau 的磷酸化增强了与微管结合的 tau 量，并抑制了 tau 的轴突运输。为了确定差异 tau 清除是否是磷酸模拟 tau 增加的原因，我们抑制了神经元中的自噬，与野生型 tau 相比，磷酸模拟 tau 的积累增加了 3 倍，而内源性 tau 不受影响。在自噬缺陷型小鼠胚胎成纤维细胞中，但在神经元中没有，磷酸突变型 tau 的蛋白酶体降解也比野生型 tau 减少。因此，自噬和蛋白酶体途径参与 tau 的降解，自噬似乎是神经元中清除磷酸化 tau 的主要途径。自噬功能障碍可能导致神经退行性疾病中 tau 的积累。
