Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington's disease
Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington's disease
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DOI：
10.1111/j.1471-4159.2012.07711.x
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发表时间：
2012-05-01
影响因子：
4.7
通讯作者：
Xifro, Xavier
中科院分区：
文献类型：
--
作者：
Anglada-Huguet, Marta;Giralt, Albert;Xifro, Xavier
转录因子Elk-1已被揭示为对毒性刺激的神经保护。在这项研究中，我们探讨了Elk-1在亨廷顿病中的神经保护能力。为此，我们使用了两个外显子-1突变亨廷顿蛋白（mhtt）小鼠模型（R6/1和R6/2），和全长mhtt纹状体细胞模型（STHDhQ 111/Q111）。对R6小鼠纹状体中Elk-1和pElk-1 Ser 383的分析显示，在疾病进展期间，Elk-1和pElk-1 Ser 383的水平增加。类似地，与野生型细胞相比，STHDhQ 111/Q111细胞中的Elk-1和pElk-1 Ser 383水平增加。此外，我们观察到一个主要的核定位的Elk-1在STHDhQ 111/Q111细胞，并在纹状体的30周龄的R6/1小鼠。核Elk-1没有与mhtt聚集体共定位，表明更高的转录活性。一致的是，敲低Elk-1降低了STHDhQ 111/Q111细胞中的立即早期基因表达，但在野生型细胞中没有。有趣的是，通过siRNA转染降低Elk-1水平促进了STHDhQ 111/Q111细胞中的细胞死亡和半胱天冬酶3裂解，但在野生型细胞中没有。总之，我们提出，增加蛋白质水平，磷酸化和核定位的麋鹿-1外显子-1和全长亨廷顿病模型中观察到的可能是一种补偿机制激活的纹状体细胞在响应的存在下的mhtt，有助于神经保护。
The transcription factor Elk-1 has been revealed as neuroprotective against toxic stimuli. In this study, we explored the neuroprotective capacity of Elk-1 in Huntingtons disease. To this aim, we used two exon-1 mutant huntingtin (mhtt) mouse models (R6/1 and R6/2), and a full-length mhtt striatal cell model (STHdhQ111/Q111). Analysis of Elk-1 and pElk-1Ser383 in the striatum of R6 mice revealed increased levels during the disease progression. Similarly, Elk-1 and pElk-1Ser383 levels were increased in STHdhQ111/Q111 cells when compared with wild-type cells. In addition, we observed a predominant nuclear localization of Elk-1 in STHdhQ111/Q111 cells, and in the striatum of 30-week-old R6/1 mice. Nuclear Elk-1 did not colocalize with mhtt aggregates, suggesting a higher transcriptional activity. In agreement, the knock-down of Elk-1 decreased immediate early genes expression in STHdhQ111/Q111 cells, but not in wild-type cells. Interestingly, reduction of Elk-1 levels by siRNAs transfection promoted cell death and caspase 3 cleavage in STHdhQ111/Q111 cells, but not in wild-type cells. In summary, we propose that increased protein levels, phosphorylation and nuclear localization of Elk-1 observed in exon-1 and full-length Huntingtons disease models could be a compensatory mechanism activated by striatal cells in response to the presence of mhtt that contributes to neuroprotection.