Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity

被引：305

作者：

Kim, Dohoon ^{[1
,2
]}

Frank, Christopher L. ^{[1
,2
]}

Dobbin, Matthew M. ^{[1
]}

Tsunemoto, Rachel K. ^{[1
]}

Tu, Weihong ^{[3
]}

Peng, Peter L. ^{[3
]}

Guan, Ji-Song ^{[1
]}

Lee, Byung-Hoon ^{[1
]}

Moy, Lily Y. ^{[1
]}

Giusti, Paola ^{[1
]}

Broodie, Nisha ^{[1
]}

Mazitschek, Ralph ^{[4
,5
]}

Delalle, Ivanna ^{[1
]}

Haggarty, Stephen J. ^{[4
,5
,6
]}

Neve, Rachael L. ^{[7
]}

Lu, YouMing ^{[3
]}

Tsai, Li-Huei ^{[1
]}

机构：

[1] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[2] Harvard Univ, Sch Med, Div Mat Sci, Boston, MA 02120 USA

[3] Univ Cent Florida, Burnett Coll Biomed Sci, Orlando, FL 32826 USA

[4] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[5] Harvard Univ, Cambridge, MA 02142 USA

[6] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[7] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA

来源：

NEURON | 2008年 / 60卷 / 05期

关键词：

D O I：

10.1016/j.neuron.2008.10.015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页码：803 / 817

页数：15

共 69 条

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