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Nat Commun. 2019 Jul 2;10(1):2906. doi: 10.1038/s41467-019-10956-w.

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

Author information

1
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China.
2
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.
3
Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
4
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China. wanggh@suda.edu.cn.

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.

PMID:
31266945
PMCID:
PMC6606620
DOI:
10.1038/s41467-019-10956-w
[Indexed for MEDLINE]
Free PMC Article

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