The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
复制标题
DOI：
10.1038/ncb2058
复制
发表时间：
2010-06-01
影响因子：
21.3
通讯作者：
Park, David S.
中科院分区：
文献类型：
--
作者：
Huang, En;Qu, Dianbo;Park, David S.
越来越多的证据表明，失调的细胞周期蛋白依赖性激酶 5 (Cdk5) 在神经元死亡中发挥着关键作用。然而，Cdk5 的致病靶点尚未完全确定。在这里，我们证明 Cdk5 激活剂 p35 直接与无嘌呤/无嘧啶核酸内切酶 1 (Ape1) 相互作用，Ape1 是 DNA 损伤后对碱基切除修复 (BER) 至关重要的蛋白质。 Cdk5 与 Ape1 Thr 232 位点磷酸化，从而降低其无嘌呤/无嘧啶 (AP) 核酸内切酶活性。在体外和体内 Ape1 磷酸化依赖于 Cdk5。磷酸化 Ape1 的核酸内切酶活性降低会导致 DNA 损伤累积并导致神经元死亡。 Ape1(WT) 和 Ape1(T232A) 的过表达（而非磷酸化模拟 Ape1（T232E））可保护神经元免受 MPP(+)/MPTP 的影响。 Ape1 的缺失会使神经元对死亡敏感。重要的是，在帕金森病和阿尔茨海默病患者的死后脑组织中也观察到磷酸化的 Ape1 增加，这表明 Ape1 磷酸化与神经退行性疾病的发病机制之间存在潜在联系。
Accumulating evidence suggests that deregulated cyclin-dependent kinase 5 (Cdk5) plays a critical part in neuronal death. However, the pathogenic targets of Cdk5 are not fully defined. Here we demonstrate that the Cdk5 activator p35 interacts directly with apurinic/apyrimidinic endonuclease 1 (Ape1), a protein crucial for base excision repair (BER) following DNA damage. Cdk5 complexes phosphorylate Ape1 at Thr 232 and thereby reduces its apurinic/apyrimidinic (AP) endonuclease activity. Ape1 phosphorylation is dependent on Cdk5 in in vitro and in vivo. The reduced endonuclease activity of phosphorylated Ape1 results in accumulation of DNA damage and contributes to neuronal death. Overexpression of Ape1(WT) and Ape1(T232A), but not the phosphorylation mimic Ape1(T232E), protects neurons against MPP(+)/MPTP. Loss of Ape1 sensitizes neurons to death. Importantly, increased phosphorylated Ape1 was also observed in post-mortem brain tissue from patients with Parkinson's and Alzheimer's diseases, suggesting a potential link between Ape1 phosphorylation and the pathogenesis of neurodegenerative diseases.