Flaherty D B, Soria J P, Tomasiewicz H G, Wood J G
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci Res. 2000 Nov 1;62(3):463-72. doi: 10.1002/1097-4547(20001101)62:3<463::AID-JNR16>3.0.CO;2-7.
Microtubules (MTs), primarily composed of alpha and beta tubulin polymers, must often work in concert with microtubule-associated proteins (MAPs) in order to modulate their functional demands. In a mature brain neuron, one of the key MAPs that resides primarily in the axonal compartment is the tau protein. Tau, in the adult human brain, is a set of six protein isoforms, whose binding affinity to MTs can be modulated by phosphorylation. In addition to the role that phosphorylation of tau plays in the "normal" physiology of neurons, hyperphosphorylated tau is the primary component of the fibrillary pathology in Alzheimer's disease (AD). Although many protein kinases are known to phosphorylate tau in vitro, the in vivo players contributing to the hyperphosphorylation of tau remain elusive. The experiments in this study attempt to define which protein kinases and protein phosphatases reside in the associated network of microtubules, thereby being strategically positioned to influence the phosphorylation of tau. Microtubule fractions are utilized to determine which of the microtubule-associated kinases most readily impacts the phosphorylation of tau at "AD-like" sites. Results from this study indicate that PKA, CK1, GSK3beta, and cdk5 associate with microtubules. Among the MT-associated kinases, GSK3beta and cdk5 most readily contribute to the ATP-induced "AD-like" phosphorylation of tau.
微管（MTs）主要由α和β微管蛋白聚合物组成，为了调节其功能需求，它们常常需要与微管相关蛋白（MAPs）协同发挥作用。在成熟的脑神经元中，主要存在于轴突区室的关键MAPs之一是tau蛋白。在成人大脑中，tau是一组六种蛋白质异构体，其与微管的结合亲和力可通过磷酸化作用进行调节。除了tau蛋白磷酸化在神经元“正常”生理过程中所起的作用外，过度磷酸化的tau是阿尔茨海默病（AD）纤维状病理的主要成分。尽管已知许多蛋白激酶在体外可使tau磷酸化，但导致tau过度磷酸化的体内作用因子仍不明确。本研究中的实验试图确定哪些蛋白激酶和蛋白磷酸酶存在于微管的相关网络中，从而在战略上能够影响tau的磷酸化。利用微管组分来确定哪种微管相关激酶最容易在“AD样”位点影响tau的磷酸化。本研究结果表明，蛋白激酶A（PKA）、细胞周期蛋白依赖性激酶1（CK1）、糖原合成酶激酶3β（GSK3β）和周期蛋白依赖性激酶5（cdk5）与微管相关。在与微管相关的激酶中，GSK3β和cdk5最容易促使ATP诱导tau发生“AD样”磷酸化。
