Tau-Induced Ca^(2+)/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation  

作　　者：Yu-Ping Wei Jin-Wang Ye Xiong Wang Li-Ping Zhu Qing-Hua Hu Qun Wang Dan Ke Qing Tian Jian-Zhi Wang 

机构地区：[1]Pathophysiology Department, Tongji Medical College,Huazhong University of Science and Technology [2]Key Laboratory of Ministry of Education for Neurological Disorders and Hubei Provincial Key Laboratory for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology

出　　处：《Neuroscience Bulletin》2018年第2期261-269,共9页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(91632305);the National Key Research and Development Program of China(2016YFC13058001)

摘　　要：Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer’s disease(AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells.Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca2+concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca2+concentration with a simultaneous increase in the phosphorylation of Ca2+/calmodulin-dependent protein kinase IV(Ca MKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca2+/Ca MKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation ofthe Ca2+/calmodulin complex abolished the okadaic acidinduced tau hyperphosphorylation in the nuclear fraction.We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca2+/Ca MKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca2+concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer's disease(AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells.Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca^(2+)concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca^(2+)concentration with a simultaneous increase in the phosphorylation of Ca^(2+)/calmodulin-dependent protein kinase IV(Ca MKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca^(2+)/Ca MKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation ofthe Ca^(2+)/calmodulin complex abolished the okadaic acidinduced tau hyperphosphorylation in the nuclear fraction.We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca^(2+)/Ca MKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca^(2+)concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.

关 键 词：Alzheimer’s disease TAU PHOSPHORYLATION Nuclear calcium signal CAMKIV 

分 类 号：R749.16[医药卫生—神经病学与精神病学]