Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.
Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.
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DOI：
10.1016/j.nbd.2014.05.012
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发表时间：
2014-09
影响因子：
6.1
通讯作者：
Chesselet MF
中科院分区：
文献类型：
--
作者：
Richter F;Gao F;Medvedeva V;Lee P;Bove N;Fleming SM;Michaud M;Lemesre V;Patassini S;De La Rosa K;Mulligan CK;Sioshansi PC;Zhu C;Coppola G;Bordet T;Pruss RM;Chesselet MF
胆固醇肟类药物TRO19622和TRO40303以线粒体外膜蛋白为靶点，在神经退行性疾病的临床前模型中具有有益的作用，因此可以进入临床试验。帕金森病（PD）中多巴胺能神经元退行性变，易发生氧化应激和线粒体功能障碍。为了深入了解TRO19622和TRO40303对体内多巴胺能神经元的神经保护潜力，我们评估了它们对激光捕获的野生型小鼠和过表达α -突触核蛋白的小鼠（Thy1-aSyn小鼠）黑质纹状体多巴胺能神经元基因表达的影响。α -突触核蛋白是家族性和散发性PD的一种蛋白。在该模型中，在纹状体多巴胺丢失出现前约10个月，幼鼠在1至4月龄时被喂食食物颗粒或对照饮食中的药物。无偏加权基因共表达网络分析（WGCNA）的转录变化揭示了胆固醇氧对野生型和转基因小鼠线粒体、细胞保护和抗氧化反应相关转录物的影响，包括应激防御（如Prdx1、Prdx2、Glrx2、Hspa9、Pink1、Drp1、Trak1）和多巴胺相关基因（Th、Ddc、Gch1、Dat、Vmat2、Drd2、Chnr6a）的转录增加。即使在这么小的年龄，转基因小鼠也显示出与线粒体功能和氧化应激相关的转录物的改变（例如Bcl-2， Bax, Casp3, Nos2），两种药物使这些改变的20%左右正常化。年轻的Thy1-aSyn小鼠表现出不同于帕金森病的运动缺陷，并且在治疗开始前就已经建立；这些缺陷并没有被胆固醇氧改善。然而，高剂量的TRO40303改善了嗅觉，并在具有挑战性的梁测试中产生了与多巴胺激动剂相同的效果，特别是增加了脚掌，这与它对多巴胺合成相关转录物的影响一致。高剂量TRO19622增加黑质α -突触核蛋白聚集；这种作用在TRO40303中未见，不一致，可能代表了其他神经退行性疾病的保护机制。总之，结果表明，虽然胆固醇肟不能改善α -突触核蛋白过表达对运动行为或病理的早期影响，但可能改善体内多巴胺能神经元的功能和恢复能力，并支持进一步研究多巴胺能细胞丧失模型的神经保护作用。
Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.
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影响因子：
11.2
作者：
Choi, Kyu Jin;Piao, Yu Ji;Kim, Sung Soo
通讯作者：
Kim, Sung Soo
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
DOI：
10.1111/j.1460-9568.2008.06346.x
发表时间：
2008-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Fleming SM;Tetreault NA;Mulligan CK;Hutson CB;Masliah E;Chesselet MF
通讯作者：
Chesselet MF
影响因子：
5.3
作者：
Guatteo, Ezia;Yee, Andrew;Lipski, Janusz
通讯作者：
Lipski, Janusz
影响因子：
15.1
作者：
Cabeza-Arvelaiz Y;Fleming SM;Richter F;Masliah E;Chesselet MF;Schiestl RH
通讯作者：
Schiestl RH