ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line.
ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line.
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ATF3 在稳定的 PC12 细胞系中发挥针对突变亨廷顿蛋白 N 末端片段毒性的保护作用。
DOI：
10.1016/j.brainres.2009.06.049
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发表时间：
2009
期刊：
影响因子：
2.9
通讯作者：
Ross,ChristopherA
中科院分区：
文献类型：
--
作者：
Liang,Yideng;Jiang,Haibing;Ratovitski,Tamara;Jie,Chunfa;Nakamura,Masayuki;Hirschhorn,RickyR;Wang,Xiaofang;Smith,WanliW;Hai,Tsonwin;Poirier,MichelleA;Ross,ChristopherA
亨廷顿病是一种进行性神经退行性疾病，由亨廷顿蛋白 N 末端附近的聚谷氨酰胺扩张引起。聚谷氨酰胺神经毒性和细胞反应的机制尚不完全清楚。我们使用可诱导的 PC12 细胞模型，通过短寡核苷酸阵列研究了基因表达谱，该模型表达具有扩展的聚谷氨酰胺 (Htt-N63-148Q) 的 N 末端亨廷顿片段。突变亨廷顿蛋白 Htt-N63 诱导细胞死亡并增加激活转录因子 3 (ATF3) 的 mRNA 和蛋白质水平。通过基于启动子的报告基因检测，突变体 Htt-N63 还显着增强了 ATF3 转录活性。 ATF3 的过表达可防止突变型 Htt-N63 毒性，敲低 ATF3 表达可降低稳定 PC12 细胞系中的 Htt-N63 毒性。这些结果表明，ATF3 在突变体 Htt-N63 诱导的毒性中发挥着关键作用，并可能成为有用的治疗靶点。
Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine expansion near the N-terminus of huntingtin. The mechanisms of polyglutamine neurotoxicity, and cellular responses are not fully understood. We have studied gene expression profiles by short oligo array using an inducible PC12 cell model expressing an N-terminal huntingtin fragment with expanded polyglutamine (Htt-N63-148Q). Mutant huntingtin Htt-N63 induced cell death and increased the mRNA and protein levels of activating transcription factor 3 (ATF3). Mutant Htt-N63 also significantly enhanced ATF3 transcriptional activity by a promoter-based reporter assay. Overexpression of ATF3 protects against mutant Htt-N63 toxicity and knocking down ATF3 expression reduced Htt-N63 toxicity in a stable PC12 cell line. These results indicated that ATF3 plays a critical role in toxicity induced by mutant Htt-N63 and may lead to a useful therapeutic target.