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Mol Neurodegener. 2015 Sep 3;10:42. doi: 10.1186/s13024-015-0036-5.

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

Wang G1,2,3, Yang H4, Yan S5,6, Wang CE7, Liu X8,9, Zhao B10, Ouyang Z11, Yin P12, Liu Z13, Zhao Y14, Liu T15, Fan N16, Guo L17, Li S18, Li XJ19,20, Lai L21.

Author information

1
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. ghwang85@gmail.com.
2
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. ghwang85@gmail.com.
3
University of Chinese Academy of Sciences, Beijing, 100049, China. ghwang85@gmail.com.
4
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. yang_huaqiang@gibh.ac.cn.
5
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. 231yansen@gmail.com.
6
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. 231yansen@gmail.com.
7
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. cwang5@emory.edu.
8
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. xdliu@genetics.ac.cn.
9
University of Chinese Academy of Sciences, Beijing, 100049, China. xdliu@genetics.ac.cn.
10
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. zhao_bentian@gibh.ac.cn.
11
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. ouyang_zhen@gibh.ac.cn.
12
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. yinpeng177@163.com.
13
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. liu_zhaoming@gibh.ac.cn.
14
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. zhao_yu531@gibh.ac.cn.
15
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. liu_tao@gibh.ac.cn.
16
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. fan_nana@gibh.ac.cn.
17
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. guo_lin@gibh.ac.cn.
18
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. sli@emory.edu.
19
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. xli2@emory.edu.
20
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. xli2@emory.edu.
21
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. lai_liangxue@gibh.ac.cn.

Abstract

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.

PMID:
26334913
PMCID:
PMC4557629
DOI:
10.1186/s13024-015-0036-5
[Indexed for MEDLINE]
Free PMC Article

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