CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington's disease.
CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington's disease.
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DOI：
10.1016/j.nbd.2009.07.014
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发表时间：
2009-11
影响因子：
6.1
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Choi YS;Lee B;Cho HY;Reyes IB;Pu XA;Saido TC;Hoyt KR;Obrietan K
在亨廷顿氏病（HD）动物模型中CREB/CRE转录途径失调的证据表明，设计用于增强CRE介导的转录的策略可能具有治疗价值。在这里，我们研究了CREB激活和抑制化学和转基因小鼠模型的HD的后果。在3-硝基丙酸（3-NP）模型中，纹状体中的CREB磷酸化激活在细胞死亡前在神经毒性“核心”区域内被有效抑制。相反，在“半影”区域检测到磷酸化CREB以及CREB调节的细胞保护基因Bcl-2的显著表达。为了检查CREB/CRE转录途径在纹状体变性中的潜在贡献作用，我们使用CREB功能丧失（A-CREB）和获得（VP 16-CREB）的转基因小鼠品系。与对照组相比，A-CREB小鼠中3-NP诱导的纹状体病变大小和运动功能障碍显著增加。相反，纹状体损伤和运动缺陷减少VP 16-CREB小鼠。此外，转基因A-CREB显著加速HD的YAC 128小鼠模型中的运动损伤。总之，这些结果表明，CREB功能在纹状体细胞应激的早期阶段丢失，并且CREB介导的转录的抑制有助于致病过程。
Evidence of dysregulation of the CREB/CRE transcriptional pathway in animal models of Huntington’s disease (HD) suggests that strategies designed to augment CRE-mediated transcription may be of therapeutic value. Here, we investigated the consequences of CREB activation and repression in chemical and transgenic mouse models of HD. In the 3-nitropropionic acid (3-NP) model, CREB phospho-activation in the striatum was potently repressed within the neurotoxic “core” region prior to cell death. Conversely, marked expression of phospho-CREB, as well the CREB-regulated cytoprotective gene Bcl-2, was detected in the “penumbral” region. To examine potential contributory roles for the CREB/CRE transcriptional pathway in striatal degeneration, we used both CREB loss- (A-CREB) and gain- (VP16-CREB) of-function transgenic mouse strains. 3-NP-induced striatal lesion size and motor dysfunction were significantly increased in A-CREB mice compared to controls. Conversely, striatal damage and motor deficits were diminished VP16-CREB mice. Furthermore, transgenic A-CREB significantly accelerated motor impairment in the YAC128 mouse model of HD. Together, these results indicate that CREB functionality is lost during the early stages of striatal cell stress and that the repression of CREB-mediated transcription contributes to the pathogenic process.
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影响因子：
4.7
作者：
Lee B;Cao R;Choi YS;Cho HY;Rhee AD;Hah CK;Hoyt KR;Obrietan K
通讯作者：
Obrietan K
影响因子：
6.1
作者：
Lee, Boyoung;Dziema, Heather;Obrietan, Karl
通讯作者：
Obrietan, Karl
影响因子：
4.8
作者：
Krönke, G;Bochkov, VN;Leitinger, N
通讯作者：
Leitinger, N
影响因子：
3.3
作者：
Fernagut, PO;Diguet, E;Tison, F
通讯作者：
Tison, F
影响因子：
3
作者：
KOH, JY;CHOI, DW
通讯作者：
CHOI, DW