Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China.
Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Nat Commun. 2019 Jul 2;10(1):2906. doi: 10.1038/s41467-019-10956-w.
A GGGGCC hexanucleotide repeat expansion in intron 1 of chromosome 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-PR) specifically in neurons. GFP-PR homozygous 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-PR heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.
9 号染色体开放阅读框 72（C9ORF72）基因中 GGGGCC 六核苷酸重复扩展是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。二肽重复蛋白（DPR）的重复相关非 ATG 翻译导致 c9FTD/ALS 的神经病理学特征。在五种 DPR 中，富含精氨酸的聚-PR 被报道为最具毒性。在这里，我们构建了一种在神经元中特异性表达聚-PR（GFP-PR）的转基因小鼠系。GFP-PR 纯合子小鼠的存活时间缩短，而杂合子小鼠则表现出运动失衡、脑重降低、浦肯野细胞和运动神经元丢失，以及小脑和脊髓的炎症。转录分析表明，在小脑，GFP-PR 杂合子小鼠表现出与突触传递相关基因的差异表达。我们的研究结果表明，GFP-PR 转基因小鼠部分模拟了 c9FTD/ALS 的神经病理学特征，并显示聚-PR 在神经退行性变中的作用。
