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

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.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.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.
Mesh Terms:
Amyotrophic Lateral Sclerosis, Animals, Animals, Genetically Modified, Central Nervous System, Cytoplasm, DNA-Binding Proteins, Disease Models, Animal, Humans, Motor Neurons, Muscular Atrophy, Nerve Tissue Proteins, Nuclear Transfer Techniques, PTB-Associated Splicing Factor, Phenotype, Protein Interaction Mapping, Protein Transport, RNA Splicing, RNA-Binding Proteins, Species Specificity, Sus scrofa, TDP-43 Proteinopathies
Mol Neurodegener
Date: Sep. 03, 2015
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