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Cell Res. 2014 Apr;24(4):464-81. doi: 10.1038/cr.2014.25. Epub 2014 Feb 28.

Species-dependent neuropathology in transgenic SOD1 pigs.

Author information

1
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
2
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
3
Department of Neurosurgery, The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
4
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
5
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
6
1] Department of Neurosurgery, The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China [2] Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia [3] The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, Yunnan 650500, China.
7
1] State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China [2] Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.

Abstract

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.

PMID:
24577199
PMCID:
PMC3975503
DOI:
10.1038/cr.2014.25
[Indexed for MEDLINE]
Free PMC Article

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