Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
复制标题
表达多聚-PR 的 C9orf72 小鼠系的运动功能障碍和神经变性
DOI：
10.1038/s41467-019-10956-w
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发表时间：
2019-07-02
影响因子：
16.6
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
--
作者：
Hao, Zongbing;Liu, Liu;Wang, Guanghui
9号染色体开放阅读框72（C9 ORF 72）基因内含子1的GGGGCC六核苷酸重复序列扩增是肌萎缩侧索硬化（ALS）和额颞叶痴呆（frontotemporal dementia）最常见的遗传病因。二肽重复序列蛋白（DPR）的重复序列相关非ATG翻译促成了c9 FTD/ALS的神经病理学特征。在五种DPR中，据报道富含精氨酸的聚PR毒性最大。在这里，我们产生了一个转基因小鼠系，表达聚PR（GFP-PR 28），特别是在神经元。GFP-PR 28纯合子小鼠显示存活时间缩短，而杂合子小鼠显示运动不平衡、脑重量减轻、浦肯野细胞和低级运动神经元丢失以及小脑和脊髓炎症。转录分析显示，在小脑中，GFP-PR 28杂合小鼠显示出与突触传递相关的基因的差异表达。我们的研究结果表明GFP-PR 28转基因小鼠部分模拟了c9 FTD/ALS的神经病理学特征，并显示了poly-PR在神经退行性变中的作用。
A GGGGCC hexanucleotide repeat expansion in intron 1 ofchromosome 9 open reading frame 72(C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to the neuropathological features of c9FTD/ALS. Among the five DPRs, arginine-rich poly-PR are reported to be the most toxic. Here, we generate a transgenic mouse line that expresses poly-PR (GFP-PR28) specifically in neurons. GFP-PR28homozygous mice show decreased survival time, while the heterozygous mice show motor imbalance, decreased brain weight, loss of Purkinje cells and lower motor neurons, and inflammation in the cerebellum and spinal cord. Transcriptional analysis shows that in the cerebellum, GFP-PR28heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR28transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.