Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease.
Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease.
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DOI：
10.1016/j.nbd.2011.02.008
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发表时间：
2011-06
影响因子：
6.1
通讯作者：
Thomas, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Tang, Bin;Seredenina, Tamara;Coppola, Giovanni;Kuhn, Alexandre;Geschwind, Daniel H.;Luthi-Carter, Ruth;Thomas, Elizabeth A.
具有扩增CAG重复序列（bbb300）的R6/2转基因小鼠比原型亲本R6/2小鼠（携带150 CAG）具有令人惊讶的延长疾病进展和更长的寿命，然而，这种表型改善的机制尚不清楚。我们比较了携带~300 CAG重复序列的R6/2转基因小鼠（R6/2Q300转基因小鼠）、携带~150 CAG重复序列的R6/2Q150转基因小鼠（R6/2Q150转基因小鼠）和同代wt对照小鼠纹状体中的基因表达谱，以确定在这些小鼠表型表达的时间过程中可能起决定作用的基因。在R6/2Q300转基因小鼠纹状体中表现出一致表达变化的顶级基因中，85%的基因表达量下降，而在R6/2Q300转基因小鼠中表现出不一致表达变化的基因多为上调基因。R6/2Q300小鼠中上调的基因与泛素连接酶复合物、细胞粘附、蛋白质折叠和蛋白质定位的建立相关。我们通过qpcr验证了R6/2Q300小鼠中后一类相关基因的表达增加，包括Lrsam1、Erp29、Nasp、Tap1、Rab9b和Pfdn5，这种变化在CAG重复数较短的R6/2小鼠中没有观察到，即使在晚期（即12周龄）。我们进一步测试了在R6/2Q300转基因小鼠中表达上调最多的两个基因Lrsam1和Erp29在过表达突变的人类亨廷顿蛋白（htt）片段的原代纹状体培养物中潜在的神经保护作用。在htt171-82Q培养中，Lrsam1的过表达阻止了neun阳性细胞体的丢失，同时减少了核htt聚集物。Erp29对该模型无明显影响。这与R6/2Q300转基因小鼠中观察到的htt包涵体定位的独特模式是一致的，在R6/2Q150转基因小鼠中，较小的细胞质包涵体代表细胞中不溶性htt的主要形式，而在R6/2Q150转基因小鼠中则观察到较大的核包涵体。我们认为，在CAG重复数大幅增加的R6/2小鼠中观察到的发病和病程延长可能是由于与蛋白质定位和清除相关的基因的差异上调所致。这些基因可能代表了减少HD患者htt聚集毒性和细胞死亡的新治疗途径，Lrsam1是一个有希望的新候选疾病修饰因子。
R6/2 transgenic mice with expanded CAG repeats (>300) have a surprisingly prolonged disease progression and longer lifespan than prototypical parent R6/2 mice (carrying 150 CAGs), however, the mechanism of this phenotype amelioration is unknown. We compared gene expression profiles in the striatum of R6/2 transgenic mice carrying ~300 CAG repeats (R6/2Q300 transgenic mice), those carrying ~150 CAG repeats (R6/2Q150 transgenic mice) and littermate wt controls in order to identify genes that may play determinant roles in the time course of phenotypic expression in these mice. Of the top genes showing concordant expression changes in the striatum of both R6/2 lines, 85% were decreased in expression, while discordant expression changes were observed mostly for genes upregulated in R6/2Q300 transgenic mice. Upregulated genes in the R6/2Q300 mice were associated with the ubiquitin ligase complex, cell adhesion, protein folding and establishment of protein localization. We qPCR-validated increases in expression of genes related to the latter category, including Lrsam1, Erp29, Nasp, Tap1, Rab9b and Pfdn5 in R6/2Q300 mice, changes that were not observed in R6/2 mice with shorter CAG repeats, even in late stages (i.e. 12 weeks of age). We further tested Lrsam1 and Erp29, the two genes showing the greatest upregulation in R6/2Q300 transgenic mice, for potential neuroprotective effects in primary striatal cultures overexpressing a mutated human huntingtin (htt) fragment. Overexpression of Lrsam1 prevented the loss of NeuN-positive cell bodies in htt171-82Q cultures, concomitant with a reduction of nuclear htt aggregates. Erp29 showed no significant effects in this model. This is consistent with the distinct pattern of htt inclusion localization observed in R6/2Q300 transgenic mice, in which smaller cytoplasmic inclusions represent the major form of insoluble htt in the cell, as opposed to large nuclear inclusions observed in R6/2Q150 transgenic mice. We suggest that the prolonged onset and disease course observed in R6/2 mice with greatly expanded CAG repeats might result from differential upregulation of genes related to protein localization and clearance. Such genes may represent novel therapeutic avenues to decrease htt aggregate toxicity and cell death in HD patients, with Lrsam1 being a promising, novel candidate disease modifier.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.0308479101
发表时间：
2004-03-09
影响因子：
11.1
作者：
Wexler, NS
通讯作者：
Wexler, NS
亨廷顿病蛋白与转录激活因子 Sp1 的相互作用
影响因子：
5.3
作者：
Li, SH;Cheng, AL;Li, XJ
通讯作者：
Li, XJ
影响因子：
4.7
作者：
Desplats, PA;Kass, KE;Thomas, EA
通讯作者：
Thomas, EA
影响因子：
64.5
作者：
Davies, SW;Turmaine, M;Bates, GP
通讯作者：
Bates, GP