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

Zongbing Hao, Liu Liu, Zhouteng Tao, Rui Wang, Haigang Ren, Hongyang Sun, Zixuan Lin, Zhixiong Zhang, Chenchen Mu, Jiawei Zhou and Guanghui Wang ()
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Zongbing Hao: College of Pharmaceutical Sciences, Soochow University
Liu Liu: College of Pharmaceutical Sciences, Soochow University
Zhouteng Tao: Chinese Academy of Sciences
Rui Wang: College of Pharmaceutical Sciences, Soochow University
Haigang Ren: College of Pharmaceutical Sciences, Soochow University
Hongyang Sun: College of Pharmaceutical Sciences, Soochow University
Zixuan Lin: College of Pharmaceutical Sciences, Soochow University
Zhixiong Zhang: College of Pharmaceutical Sciences, Soochow University
Chenchen Mu: College of Pharmaceutical Sciences, Soochow University
Jiawei Zhou: Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Guanghui Wang: College of Pharmaceutical Sciences, Soochow University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10956-w

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