Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington's disease.
Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington's disease.
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DOI：
10.1186/1471-2199-9-84
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发表时间：
2008-10-09
影响因子：
--
通讯作者：
van Ommen GB
中科院分区：
文献类型：
--
作者：
van Roon-Mom WM;Pepers BA;'t Hoen PA;Verwijmeren CA;den Dunnen JT;Dorsman JC;van Ommen GB
亨廷顿病是一种进行性常染色体显性遗传性神经退行性疾病，由HD或亨廷顿病基因CAG重复扩增引起。尽管对患者和动物组织的微阵列研究提供了有价值的信息，但在疾病晚期，突变的亨廷顿蛋白的主要作用将不可避免地被次要过程所掩盖。因此，细胞模型有助于研究突变的亨廷顿蛋白的早期直接影响。在可诱导的亨廷顿病PC12模型中，研究了聚集体可见前后的mRNA变化，以确定可能在亨廷顿病早期病理中发挥作用的基因组。在聚集之前，基因表达以上调为主，而在聚集可见后，下调和上调的程度相同。在凝聚体可见后，伴随着培养物中多巴胺水平的下调，多巴胺生物合成基因的下调，表明该模型用于识别功能相关的途径。此外，抗氧化剂Nrf2-ARE途径的基因上调，可能是一种保护机制。与此同时，我们发现了可能导致氧化应激和损伤增加的基因变化。基因表达上调在HD病理中可能比之前认识到的更重要。此外，考虑到氧化应激和神经炎症的致病影响，Nrf2-ARE信号通路构成了HD新的有吸引力的治疗靶点。
Huntington's disease is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD or Huntington's disease gene. Although micro array studies on patient and animal tissue provide valuable information, the primary effect of mutant huntingtin will inevitably be masked by secondary processes in advanced stages of the disease. Thus, cell models are instrumental to study early, direct effects of mutant huntingtin. mRNA changes were studied in an inducible PC12 model of Huntington's disease, before and after aggregates became visible, to identify groups of genes that could play a role in the early pathology of Huntington's disease. Before aggregation, up-regulation of gene expression predominated, while after aggregates became visible, down-regulation and up-regulation occurred to the same extent. After aggregates became visible there was a down-regulation of dopamine biosynthesis genes accompanied by down-regulation of dopamine levels in culture, indicating the utility of this model to identify functionally relevant pathways. Furthermore, genes of the anti-oxidant Nrf2-ARE pathway were up-regulated, possibly as a protective mechanism. In parallel, we discovered alterations in genes which may result in increased oxidative stress and damage. Up-regulation of gene expression may be more important in HD pathology than previously appreciated. In addition, given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway constitutes a new attractive therapeutic target for HD.
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影响因子：
4.8
作者：
Lee, JM;Shih, AY;Johnson, JA
通讯作者：
Johnson, JA
影响因子：
2.2
作者：
GRAHAM, PE;SMYTHE, GA;LAZARUS, L
通讯作者：
LAZARUS, L
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
3.5
作者：
Cong, SY;Pepers, BA;Dorsman, JC
通讯作者：
Dorsman, JC