Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.
Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.
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DOI：
10.1016/j.neuron.2016.02.011
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发表时间：
2016-03-16
期刊：
影响因子：
16.2
通讯作者：
Orr HT
中科院分区：
文献类型：
--
作者：
Ingram M;Wozniak EAL;Duvick L;Yang R;Bergmann P;Carson R;O'Callaghan B;Zoghbi HY;Henzler C;Orr HT
SCA1是一种致命的神经退行性疾病，由编码ATXN1蛋白中多谷氨酰胺延伸的CAG扩张引起。我们使用RNA测序来分析患有共济失调和进行性病理的Pcp2-ATXN1[82Q]小鼠和没有浦肯野细胞进行性病理的共济失调的Pcp2-ATXN1[30Q]D776动物的小脑基因表达。对小脑表达数据的加权基因共表达网络分析揭示了两个与疾病显著相关的基因网络，并具有与疾病进展相关的表达谱ATXN1[82Q]浦肯野细胞。品红模块提供了反映浦肯野细胞疾病进展的受抑制转录程序的特征，而LT黄色模块反映了浦肯野细胞以及其他小脑细胞类型对疾病反应而激活的转录程序。此外，我们发现，在Pcp2-ATXN1[30Q]D776小鼠中，CCK的上调以及随后与Cock1受体的相互作用可能是Pcp2-ATXN1[30Q]D776小鼠缺乏进行性浦肯野细胞病理的原因。
SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module, reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice.