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Author Notes:

Email Address: Guohao Wang : ghwang85@gmail.com

SL X-JL and LL designed and supervised experiments. G W, SY, C-E W, XL, PY performed molecular and biochemical studies.

H Y, BZ, ZO, ZL YZ, TL performed experiments on generation of transgenic pigs. N F and LG provided technical assistance.

X-JL wrote the manuscript with help of GW and HY All authors read and approved the final manuscript.

We would like to thank the staffs of the pig farm for animal husbandry and assistance in the behavioral tasks, the neuropathology/histochemistry core of Emory University for providing human brain tissue samples, and Dr. V.M. Kalscheuer for providing the PSF plasmid.

We thank Cheryl Strauss for critically reading this manuscript.

The authors declare that they have no competing interests.

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Research Funding:

This work was supported by grants from the National Basic Research Program of China (973 program) (2011CB944203), the Natural Science Foundation of China (31071293) awarded to L.L.

National Institutes of Health (NS036232, NS041669, and NS045016) to X.L. and S.L.

Keywords:

  • TDP-43
  • PSF
  • NeuN
  • NMHC II-B
  • ALS
  • transgenic Pig

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

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Journal Title:

Molecular Neurodegeneration

Volume:

Volume 10, Number 1

Publisher:

, Pages 42-42

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© Wang et al. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution, public display, and publicly performance, making multiple copies, distribution of derivative works, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact.

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