Ingram Melissa, Wozniak Emily A L, Duvick Lisa, Yang Rendong, Bergmann Paul, Carson Robert, O'Callaghan Brennon, Zoghbi Huda Y, Henzler Christine, Orr Harry T
Institute for Translational Neuroscience, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
Department of Genetics, Cell Biology, and Development, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455.
Neuron. 2016 Mar 16;89(6):1194-1207. doi: 10.1016/j.neuron.2016.02.011. Epub 2016 Mar 3.
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 in 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.
脊髓小脑共济失调1型（SCA1）是一种致命的神经退行性疾病，由编码蛋白质ATXN1中多聚谷氨酰胺延伸的CAG重复序列扩增引起。我们使用RNA测序对患有共济失调和进行性病理变化的Pcp2-ATXN1[82Q]小鼠以及在没有浦肯野细胞进行性病理变化的情况下患有共济失调的Pcp2-ATXN1[30Q]D776动物的小脑基因表达进行了分析。对小脑表达数据进行加权基因共表达网络分析，发现了两个与疾病显著相关的基因网络，其表达谱与ATXN1[82Q]浦肯野细胞中的疾病进展相关。品红色模块提供了反映浦肯野细胞疾病进展的转录程序受抑制的特征，而浅黄模块反映了浦肯野细胞以及其他小脑细胞类型中因疾病而激活的转录程序。此外，我们发现胆囊收缩素（Cck）的上调以及随后与Cck1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变化的原因。
