Species-dependent neuropathology in transgenic SOD1 pigs

Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs...

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Bibliographic Details
Published in:Cell research 2014-04, Vol.24 (4), p.464-481
Main Authors: Yang, Huaqiang, Wang, Guohao, Sun, Haitao, Shu, Runzhe, Liu, Tao, Wang, Chuan-En, Liu, Zhaoming, Zhao, Yu, Zhao, Bentian, Ouyang, Zhen, Yang, Dongshan, Huang, Jiao, Zhou, Yueling, Li, Shihua, Jiang, Xiaodan, Xiao, Zhicheng, Li, Xiao-Jiang, Lai, Liangxue
Format: Article
Language:English
Subjects:
Alanine - genetics
Amino Acid Substitution
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - pathology
Animals
Animals, Genetically Modified
Brain - metabolism
Brain - pathology
Disease Models, Animal
DNA-Binding Proteins
Glycine - genetics
Heterogeneous-Nuclear Ribonucleoproteins - metabolism
Humans
Mice
Original
Phenotype
RNA-Binding Proteins
Species Specificity
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxide Dismutase-1
Swine - genetics
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Summary:Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose- and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.
ISSN:1001-0602
1748-7838
DOI:10.1038/cr.2014.25