p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity
p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity
复制标题
DOI：
10.1073/pnas.1212914109
复制
发表时间：
2012-12-04
影响因子：
11.1
通讯作者：
Lew, John
中科院分区：
文献类型：
--
作者：
Zhang, Lingyan;Liu, Wen;Lew, John
细胞周期蛋白依赖性激酶5(CDK5)与其激活剂p35(35 kDa蛋白)形成的复合体对哺乳动物早期神经发育是必不可少的。然而，内源性p35到p25的切割与神经元死亡和神经退行性疾病有关。在这里，我们展示了编码p35 N-末端结构域的多肽(p10‘)对CDK5/p25诱导的神经元毒性具有保护作用。P10‘还防止神经毒素1-甲基-4-苯基吡啶(MPP+)处理的神经元死亡，MPP+诱导动物内源性p35转换为p25，以及帕金森病(PD)样症状。MPP+可诱导依赖于CDK5/p25的过氧化还蛋白2(Prx2)的磷酸化，从而抑制其过氧化还原酶的活性和活性氧自由基(ROS)的积累。我们发现p10‘的表达抑制了Prx2的磷酸化和神经元中ROS的积累。此外，p10‘抑制了p25诱导的与神经元死亡相关的Ki67抗体(Ki67)和组蛋白H_2AX(Gamma H_2AX)抗原的出现，它们分别是细胞周期活性和DNA双链断裂的经典标志。我们的结果表明，p10(10 kDa的蛋白)是p35中一个独特的存活区，对神经元中正常的CDK5/p35功能是必不可少的。在体内，p10结构域的缺失会导致CDK5/p25的毒性和神经变性。
Cyclin-dependent kinase 5(CDK5) in complex with its activator, p35 (protein of 35 kDa), is essential for early neurodevelopment in mammals. However, endogenous cleavage of p35 to p25 is associated with neuron death and neurodegenerative disease. Here we show that a peptide (p10') encoding the N-terminal domain of p35 protects against CDK5/p25-induced toxicity in neurons. p10' also prevented the death of neurons treated with the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), which induces conversion of endogenous p35 to p25, and Parkinson disease (PD)-like symptoms in animals. MPP+ induces CDK5/p25-dependent phosphorylation of peroxiredoxin 2 (Prx2), resulting in inhibition of its peroxireductase activity and accumulation of reactive oxygen species (ROS). We found that p10' expression inhibited both Prx2 phosphorylation and ROS accumulation in neurons. In addition, p10' inhibited the p25-induced appearance of antigen of the Ki67 antibody (Ki67) and phosphohistone H2AX (gamma H2AX), classic markers of cell cycle activity and DNA double-strand breakage, respectively, associated with neuron death. Our results suggest that p10 (protein of 10 kDa) is a unique prosurvival domain in p35, essential for normal CDK5/p35 function in neurons. Loss of the p10 domain results in CDK5/p25 toxicity and neurodegeneration in vivo.