Kim Dohoon, Frank Christopher L, Dobbin Matthew M, Tsunemoto Rachel K, Tu Weihong, Peng Peter L, Guan Ji-Song, Lee Byung-Hoon, Moy Lily Y, Giusti Paola, Broodie Nisha, Mazitschek Ralph, Delalle Ivanna, Haggarty Stephen J, Neve Rachael L, Lu Youming, Tsai Li-Huei
Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Neuron. 2008 Dec 10;60(5):803-17. doi: 10.1016/j.neuron.2008.10.015.
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 histone deacetylase 1 (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 activity 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 pathological signaling pathway illustrating 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.
异常的细胞周期活动和DNA损伤正成为各种神经退行性疾病中的重要病理组成部分。然而，其潜在机制尚不清楚。在这里，我们表明，p25/Cdk5对组蛋白脱乙酰酶1（HDAC1）活性的失调会诱导异常的细胞周期活动和双链DNA断裂，从而导致神经毒性。在神经退行性疾病的转基因模型中，p25/Cdk5活性引发了在神经元死亡之前的细胞周期活动和双链DNA断裂。p25/Cdk5对HDAC1活性的抑制被确定为这些事件的潜在机制，并且HDAC1功能获得为培养的神经元和缺血体内模型中的DNA损伤和神经毒性提供了有效的保护。我们的研究结果概述了一条病理信号通路，阐明了在成年神经元中维持HDAC1活性的重要性。这条通路构成了异常细胞周期活动与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的潜在靶点。
