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

• Authors: Guohao Wang, Chinese Academy of Sciences; Huaqiang Yang, Chinese Academy of Sciences; Sen Yan, Chinese Academy of Sciences; Chuan-En Wang, Emory University; Xudong Liu, Chinese Academy of Sciences; Bentian Zhao, Chinese Academy of Sciences; Zhen Ouyang, Chinese Academy of Sciences; Peng Yin, Chinese Academy of Sciences; Zhaoming Liu, Chinese Academy of Sciences; Yu Zhao, Chinese Academy of Sciences; Tao Liu, Chinese Academy of Sciences; Nana Fan, Chinese Academy of Sciences; Lin Guo, Chinese Academy of Sciences; Shihua Li, Emory University; Xiao-Jiang Li, Emory University; Liangxue Lai, Chinese Academy of Sciences
• Journal Title: Molecular Neurodegeneration
• Volume: Volume 10, Number 1
• Publisher: BioMed Central | 2015, Pages 42-42
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s13024-015-0036-5
• Subjects: Biology, Neuroscience; Health Sciences, General
• Keywords: TDP-43; PSF; NeuN; NMHC II-B; ALS; transgenic Pig

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.