Cytoplasmic mislocalization of RNA splicing factors and aberrant neuronal gene splicing in TDP-43 transgenic pig brain

Molecular Neurodegeneration

Liangxue Lai³  Xiao-Jiang Li⁴  Shihua Li⁴  Lin Guo³  Nana Fan³  Tao Liu³  Yu Zhao³  Zhaoming Liu³  Peng Yin²  Zhen Ouyang³  Bentian Zhao³  Xudong Liu¹  Chuan-En Wang⁴  Sen Yan⁴  Huaqiang Yang³  Guohao Wang¹ 

[1] University of Chinese Academy of Sciences, Beijing 100049, China;State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;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 510530, China;Department of Human Genetics, Emory University School of Medicine, Atlanta 30322, GA, USA

关键词: transgenic Pig;    ALS;    NMHC II-B;    NeuN;    PSF;    TDP-43;   

Others  :  1224814
DOI  :  10.1186/s13024-015-0036-5

 received in 2015-04-12, accepted in 2015-08-10,  发布年份 2015

【 摘 要 】

Background

TAR DNA-binding protein 43 (TDP-43) is a nuclear protein, but it is redistributed in the neuronal cytoplasm in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Because small transgenic animal models often lack cytoplasmic TDP-43, how the cytoplasmic accumulation of TDP-43 contributes to these diseases remains unclear. The current study is aimed at studying the mechanism of cytoplasmic pathology of TDP-43.

Results

We established transgenic pigs expressing mutant TDP-43 (M337V). This pig model shows severe phenotypes and early death. We found that transgenic TDP-43 is also distributed in the cytoplasm of neuronal cells in the spinal cord and brain. Transgenic TDP-43 interacts with PSF, an RNA splicing factor that associates with NeuN to regulate neuronal RNA splicing. The interaction of TDP-43, PSF and NeuN causes PSF and NeuN mislocalize into the neuronal cytoplasm in transgenic pigs. Consistently, abnormal PSF-related neuronal RNA splicing is seen in TDP-43 transgenic pigs. The cytoplasmic localization of PSF and NeuN as well as abnormal PSF-related neuronal RNA splicing was also found in ALS patient brains.

Conclusion

Our findings from a large mammalian model suggest that cytoplasmic mutant TDP-43 could reduce the nuclear function of RNA splicing factors, contributing to neuropathology.

【 授权许可】

   
2015 Wang et al.

【 图 表 】

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