A gene expression phenotype in lymphocytes from Friedreich ataxia patients.
A gene expression phenotype in lymphocytes from Friedreich ataxia patients.
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DOI：
10.1002/ana.22526
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发表时间：
2011-11
影响因子：
11.2
通讯作者：
Geschwind, Daniel H.
中科院分区：
文献类型：
--
作者：
Coppola, Giovanni;Burnett, Ryan;Perlman, Susan;Versano, Revital;Gao, Fuying;Plasterer, Heather;Rai, Myriam;Sacca, Francesco;Filla, Alessandro;Lynch, David R.;Rusche, James R.;Gottesfeld, Joel M.;Pandolfo, Massimo;Geschwind, Daniel H.
神经退行性疾病患者外周组织中的基因表达研究可以深入了解疾病的发病机制，并确定潜在的生物标志物，这是神经退行性疾病转化研究的重要目标。弗里德赖希共济失调（FRDA）是一种慢性神经退行性疾病，由共济失调蛋白（一种广泛表达的蛋白质）的转录减少引起。我们研究了FRDA患者和携带者的体外淋巴细胞，以确定外周基因表达表型。与疾病状态相关的外周生物标志物对于评估药物疗效非常有价值，并且可以提供新的病理生理学见解。我们的特点是基因表达谱在外周血单核细胞（PBMC）从FRDA患者，与对照组和相关载体相比。在用增加共济失调蛋白水平的化合物体外处理之前和之后研究细胞。使用定量实时PCR和附加的微阵列来确认多个独立系列中的核心基因集。我们确定了一个子集的基因改变的细胞从病理性共济失调蛋白缺乏症患者和这些基因的核心集被证实在独立的系列。基因表达的变化与线粒体、脂质代谢、细胞周期和DNA修复有关，与FRDA已知的病理生理学一致。我们评估了多种化合物（HDAC抑制剂）对该推定的生物标志物集的体外作用，并发现该生化表型根据药物功效而改善。Frataxin下调与PBMC中基因表达的强烈变化相关，提供了致病性见解和核心基因子集，如果在体内验证，可以用作外周生物标志物。
Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We characterized the gene expression profiles in peripheral blood mononuclear cells (PBMCs) from FRDA patients, compared with controls and related carriers. Cells were studied both before and after in vitro treatment with compounds that increase frataxin levels. Quantitative real-time PCR and additional microarrays were used to confirm a core set of genes in multiple independent series. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker.
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DOI：
10.1042/bj20101116
发表时间：
2010-11-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Thierbach R;Drewes G;Fusser M;Voigt A;Kuhlow D;Blume U;Schulz TJ;Reiche C;Glatt H;Epe B;Steinberg P;Ristow M
通讯作者：
Ristow M
Frataxin缺乏症的功能基因组分析揭示了组织特异性的改变，并将PPARGAMMA途径鉴定为弗里德里希共济失调的治疗靶标。
影响因子：
3.5
作者：
Coppola G;Marmolino D;Lu D;Wang Q;Cnop M;Rai M;Acquaviva F;Cocozza S;Pandolfo M;Geschwind DH
通讯作者：
Geschwind DH
DOI：
10.1073/pnas.0611631104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Pomplun, Doreen;Voigt, Anja;Ristow, Michael
通讯作者：
Ristow, Michael
影响因子：
3.5
作者：
Harris, Janelle L.;Jakob, Burkhard;Lavin, Martin F.
通讯作者：
Lavin, Martin F.
影响因子：
4.5
作者：
Haugen, Astrid C.;Di Prospero, Nicholas A.;Van Houten, Bennett
通讯作者：
Van Houten, Bennett