title: Species-dependent neuropathology in transgenic SOD1 pigs.
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.
authors.affiliation: 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.
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Haitao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Runzhe
authors.initials: R
authors.lastname: Shu
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Chuan-En
authors.initials: CE
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Bentian
authors.initials: B
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: 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.
authors.forename: Dongshan
authors.initials: D
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jiao
authors.initials: J
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yueling
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liangxue
authors.initials: L
authors.lastname: Lai
mesh_terms: D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005998:Glycine / Q000235:genetics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D010641:Phenotype; D016601:RNA-Binding Proteins; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013552:Swine / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C094604:PCBP1 protein, human; D016601:RNA-Binding Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine; D005998:Glycine