Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.
Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.
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DOI：
10.1016/j.neuron.2008.10.015
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发表时间：
2008-12-10
期刊：
影响因子：
16.2
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Kim D;Frank CL;Dobbin MM;Tsunemoto RK;Tu W;Peng PL;Guan JS;Lee BH;Moy LY;Giusti P;Broodie N;Mazitschek R;Delalle I;Haggarty SJ;Neve RL;Lu Y;Tsai LH
异常的细胞周期活性和DNA损伤正在成为各种神经退行性疾病的重要病理组成部分。然而，其基本机制知之甚少。在这里，我们表明，HDAC 1活性失调的p25/Cdk 5诱导异常的细胞周期活动和双链DNA断裂，导致神经毒性。在神经退行性变的转基因模型中，p25/Cdk 5活性引起细胞周期重入和双链DNA断裂，这是神经元死亡之前。通过p25/Cdk 5抑制HDAC 1活性被确定为这些事件的潜在机制，并且HDAC 1功能获得提供了对培养的神经元和缺血的体内模型中的DNA损伤和神经毒性的有效保护。我们的研究结果概述了一种新的病理信号通路，说明了维持HDAC 1活性在成年神经元中的重要性。该途径构成异常细胞周期活性和DNA损伤之间的分子联系，并且是针对涉及神经元死亡的疾病和病症的治疗剂的潜在靶标。
Aberrant cell cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of HDAC1 activity by p25/Cdk5 induces aberrant cell cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell cycle reentry and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain-of-function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a novel pathological signaling pathway which illustrates the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.
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影响因子：
11.4
作者：
Kim, Dohoon;Nguyen, Minh Dang;Tsai, Li-Huei
通讯作者：
Tsai, Li-Huei
DOI：
10.1073/pnas.89.4.1194
发表时间：
1992-02-15
影响因子：
11.1
作者：
ALUBAIDI, MR;HOLLYFIELD, JG;BAEHR, W
通讯作者：
BAEHR, W
影响因子：
16.2
作者：
Fischer, A;Sananbenesi, F;Tsai, LH
通讯作者：
Tsai, LH
影响因子：
5
作者：
Hayashi, T;Sakai, K;Abe, K
通讯作者：
Abe, K
影响因子：
64.8
作者：
Klein, JA;Longo-Guess, CM;Ackerman, SL
通讯作者：
Ackerman, SL