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

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...

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Autores principales: Hao, Zongbing, Liu, Liu, Tao, Zhouteng, Wang, Rui, Ren, Haigang, Sun, Hongyang, Lin, Zixuan, Zhang, Zhixiong, Mu, Chenchen, Zhou, Jiawei, Wang, Guanghui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606620/
https://www.ncbi.nlm.nih.gov/pubmed/31266945
http://dx.doi.org/10.1038/s41467-019-10956-w
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author Hao, Zongbing
Liu, Liu
Tao, Zhouteng
Wang, Rui
Ren, Haigang
Sun, Hongyang
Lin, Zixuan
Zhang, Zhixiong
Mu, Chenchen
Zhou, Jiawei
Wang, Guanghui
author_facet Hao, Zongbing
Liu, Liu
Tao, Zhouteng
Wang, Rui
Ren, Haigang
Sun, Hongyang
Lin, Zixuan
Zhang, Zhixiong
Mu, Chenchen
Zhou, Jiawei
Wang, Guanghui
author_sort Hao, Zongbing
collection PubMed
description 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(28)) specifically in neurons. GFP-PR(28) 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(28) heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR(28) transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.
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spelling pubmed-66066202019-07-05 Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR Hao, Zongbing Liu, Liu Tao, Zhouteng Wang, Rui Ren, Haigang Sun, Hongyang Lin, Zixuan Zhang, Zhixiong Mu, Chenchen Zhou, Jiawei Wang, Guanghui Nat Commun Article 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(28)) specifically in neurons. GFP-PR(28) 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(28) heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR(28) transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration. Nature Publishing Group UK 2019-07-02 /pmc/articles/PMC6606620/ /pubmed/31266945 http://dx.doi.org/10.1038/s41467-019-10956-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hao, Zongbing
Liu, Liu
Tao, Zhouteng
Wang, Rui
Ren, Haigang
Sun, Hongyang
Lin, Zixuan
Zhang, Zhixiong
Mu, Chenchen
Zhou, Jiawei
Wang, Guanghui
Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title_full Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title_fullStr Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title_full_unstemmed Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title_short Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
title_sort motor dysfunction and neurodegeneration in a c9orf72 mouse line expressing poly-pr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606620/
https://www.ncbi.nlm.nih.gov/pubmed/31266945
http://dx.doi.org/10.1038/s41467-019-10956-w
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