Rat Model of Cockayne Syndrome Neurological Disease
Rat Model of Cockayne Syndrome Neurological Disease
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科凯恩综合征神经系统疾病大鼠模型
DOI：
10.1016/j.celrep.2019.09.028
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Wang Yuming
中科院分区：
文献类型：
--
作者：
Xu Yingying;Wu Zhenzhen;Liu Lingyun;Liu Jiena;Wang Yuming
Cockayne综合征(CS)是一种罕见的遗传性神经发育障碍，以核苷酸切除DNA修复(TC-NER)转录偶联亚途径缺陷为特征。Cockayne综合征B(CSB)基因突变影响基础转录，这被认为是CS神经功能障碍的主要原因。在这里，我们通过模仿CSB基因的无义突变来产生一个大鼠模型。与CSB−/−小鼠模型相比，CSB缺陷大鼠的大脑受到更深刻的影响。小脑皮质有明显的萎缩和髓鞘萎缩。可见小脑和畸形的海马体的异常叶状结构。白质呈高胶质纤维酸性蛋白(GFAP)染色，提示反应性星形胶质细胞增生症。RNA测序(RNA-seq)分析表明，CSB缺陷影响了数百个基因的表达，其中许多是神经元基因，这表明转录失调可能导致CSB大鼠模型中出现的神经系统疾病。
Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in transcription-coupled subpathway of nucleotide excision DNA repair (TC-NER). Mutation of the Cockayne syndrome B (CSB) gene affects basal transcription, which is considered a major cause of CS neurologic dysfunction. Here, we generate a rat model by mimicking a nonsense mutation in theCSBgene. In contrast to that of theCsb−/−mouse models, the brains of the CSB-deficient rats are more profoundly affected. The cerebellar cortex shows significant atrophy and dysmyelination. Aberrant foliation of the cerebellum and deformed hippocampus are visible. The white matter displays high glial fibrillary acidic protein (GFAP) staining indicative of reactive astrogliosis. RNA sequencing (RNA-seq) analysis reveals that CSB deficiency affects the expression of hundreds of genes, many of which are neuronal genes, suggesting that transcription dysregulation could contribute to the neurologic disease seen in the CSB rat models.