Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR

被引：58
|
作者：
Hao, Zongbing [1 ,2 ]
Liu, Liu [1 ,2 ]
Tao, Zhouteng [3 ]
Wang, Rui [1 ,2 ]
Ren, Haigang [1 ,2 ]
Sun, Hongyang [1 ,2 ]
Lin, Zixuan [1 ,2 ]
Zhang, Zhixiong [1 ,2 ]
Mu, Chenchen [1 ,2 ]
Zhou, Jiawei [4 ]
Wang, Guanghui [1 ,2 ]
机构：
[1] Soochow Univ, Coll Pharmaceut Sci, Jiangsu Key Lab Neuropsychiat Dis, Lab Mol Neuropathol, Suzhou 215123, Jiangsu, Peoples R China
[2] Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Jiangsu, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China
[4] Chinese Acad Sci, Shanghai Inst Biol Sci, Ctr Excellence Brain Sci, Inst Neurosci,State Key Lab Neurosci, Shanghai 200031, Peoples R China
来源：
NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期
基金：
中国国家自然科学基金;
关键词：
HEXANUCLEOTIDE REPEAT EXPANSION; AMYOTROPHIC-LATERAL-SCLEROSIS; RNA FOCI; PROTEINS; TDP-43; PATHOLOGY; TOXICITY; DEGENERATION; INFLAMMATION; INCLUSIONS;
D O I：
10.1038/s41467-019-10956-w
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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-PR28) specifically in neurons. GFP-PR28 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-PR28 heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR28 transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.
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收藏
页数：11
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