Study of the effect of Protein Kinase CK2 alpha prime in the transcriptional deficits associated with Huntington's disease

Protein kinase CK2 alpha prime (CK2a') is preferentially upregulated in the striatum of patients with HD and in different cellular and mouse models of HD. CK2a' happloinsufficiency in the zQ175 HD mouse model restored several HD-like phenotypes. We hypothesized that CK2a' neuronal up-regulation is linked to key transcriptional alterations in the zQ175 mouse model. We found that CK2a' haploinsufficiency rescued the expression of genes associated with synaptogenesis and glutamatergic signaling whose upstream regulator seems to be alpha-synuclein. These transcriptomic studies revealed a conection between CK2a', alpha-synuclein dysfunction and transcriptional changes in key signaling pathways. Striatum transcriptional profiles in zQ175 mice with and without one allele of CK2a'. RNA-seq analyses in samples obtained from the striatum of 12-14 months old mice using four different genotypes: WT, CK2a' (+/-), zQ175 and zQ175:CK2a'(+/-). All mice are in the C57BL/6 background. Animals were anesthesized with Avertin and intracardially perfused with Heparin+PBS. Brains were dissected and striatum samples were flash frozen in N2 prior to RNA extraction.蛋白激酶CK2α'（Protein kinase CK2 alpha prime，CK2a'）在亨廷顿舞蹈症（Huntington's Disease, HD）患者的纹状体，以及多种HD细胞模型与小鼠模型中呈优先上调表达。在zQ175 HD小鼠模型中，CK2a'单倍剂量不足可恢复多种HD样表型。我们推测，CK2a'的神经元上调表达与zQ175小鼠模型中的关键转录组改变存在关联。研究发现，CK2a'单倍剂量不足可挽救与突触发生及谷氨酸能信号通路相关的基因表达，此类基因的上游调控因子疑似为α-突触核蛋白（alpha-synuclein）。本转录组学研究揭示了CK2a'、α-突触核蛋白功能异常与关键信号通路转录改变之间的关联。本数据集涵盖携带与不携带单拷贝CK2a'等位基因的zQ175小鼠纹状体转录组图谱。针对12~14月龄小鼠纹状体样本开展RNA测序（RNA-seq）分析，共设置四种基因型组别：野生型（WT）、CK2a'单倍剂量不足型（CK2a' +/-）、zQ175型以及zQ175:CK2a'(+/-)型。所有实验小鼠均为C57BL/6背景品系。实验动物经阿佛丁（Avertin）麻醉后，以肝素+磷酸盐缓冲液（Heparin+PBS）进行心脏灌流。处死后剥离脑组织，分离纹状体样本并置于液氮（N2）中快速冷冻，随后开展RNA提取操作。