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- Title
Cytoplasmic mislocalization of RNA splicing factors and aberrant neuronal gene splicing in TDP-43 transgenic pig brain.
- Authors
Guohao Wang; Huaqiang Yang; Sen Yan; Chuan-En Wang; Xudong Liu; Bentian Zhao; Zhen Ouyang; Peng Yin; Zhaoming Liu; Yu Zhao; Tao Liu; Nana Fan; Lin Guo; Shihua Li; Xiao-Jiang Li; Liangxue Lai
- 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.
- Subjects
DNA-binding proteins; CYTOPLASM; AMYOTROPHIC lateral sclerosis; FRONTOTEMPORAL lobar degeneration; TRANSGENIC animals
- Publication
Molecular Neurodegeneration, 2015, Vol 10, Issue 1, p1
- ISSN
1750-1326
- Publication type
Article
- DOI
10.1186/s13024-015-0036-5