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.
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Acknowledgements
This work was supported by the National Basic Research Program of China (973 program, 2011CB944203), the National Natural Science Foundation of China (31071293) to LL; the National Institutes of Health (NS036232, NS041669 and NS045016) to XL and SL; Talent Program of Yunnan Province, China, and The Professorial Fellowship of Monash University, Australia to ZX; the National Natural Science Foundation of China (81171179, 81272439), Key Sci-Tech Research Projects of Guangdong Province, China (2008A030201019) to XJ, and The State Key Laboratory of Molecular Developmental Biology, China. We would like to thank the staffs of the pig farm for animal husbandry and assistance in the behavioral tasks. We thank Cheryl Strauss for critically reading this manuscript.
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Supplementary information
Supplementary information, Figure S1
Generation of hSOD1 transgenic piglets. (PDF 166 kb)
Supplementary information, Figure S2
Muscle atrophy in hSOD1 transgenic pig. (PDF 225 kb)
Supplementary information, Figure S3
Loss of neuronal cells in the spinal cord of hSOD1 transgenic pigs. (PDF 452 kb)
Supplementary information, Figure S4
Axonal degeneration in hSOD1 transgenic pig. (PDF 509 kb)
Supplementary information, Table S1
Copy numbers of the mutant hSOD1 gene in transgenic pigs. (PDF 82 kb)
Supplementary information, Table S2
Body weight of hSOD1 transgenic and WT pigs. (PDF 112 kb)
Supplementary information, Movie S1
Treadmill running test of a WT pig at the age of 16 months using the fixed speed mode. (MOV 9357 kb)
Supplementary information, Movie S2
Treadmill running test of TG-11 pig at the age of 16 months using the fixed speed mode. (MOV 9327 kb)
Supplementary information, Movie S3
Treadmill running test of a WT pig at the age of 18 months using the accelerating speed mode. (MOV 9488 kb)
Supplementary information, Movie S4
Treadmill running test of TG-11 pig at the age of 18 months using the accelerating speed mode. (MOV 9211 kb)
Supplementary information, Data S1
Methods (PDF 473 kb)
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Yang, H., Wang, G., Sun, H. et al. Species-dependent neuropathology in transgenic SOD1 pigs. Cell Res 24, 464–481 (2014). https://doi.org/10.1038/cr.2014.25
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DOI: https://doi.org/10.1038/cr.2014.25
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