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

Molecular Neurodegeneration
Guohao WangLiangxue Lai

Abstract

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 redu...Continue Reading

References

Mar 1, 1993·Genes & Development·J G PattonB Nadal-Ginard
Jul 8, 1999·Current Opinion in Cell Biology·A M Krecic, M S Swanson
Jan 25, 2005·Journal of Neurochemistry·David AmparanJane E Ishmael
May 1, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Isabel Tapia-PáezJuha Kere
Oct 24, 2008·The Journal of Biological Chemistry·Gaurav BajajJane E Ishmael
Oct 8, 2009·Human Molecular Genetics·G Scott PesiridisJohn Q Trojanowski
Oct 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Iga WegorzewskaRobert H Baloh
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sami J BarmadaSteven Finkbeiner
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hans WilsSamir Kumar-Singh
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yan LiJane Y Wu
Mar 18, 2010·Nature Reviews. Neurology·Alice S Chen-PlotkinJohn Q Trojanowski
Jun 10, 2010·Human Molecular Genetics·Peter E A AshChristopher D Link
Jul 14, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shuo-Chien LingDon W Cleveland
Aug 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Aibing WangRobert S Adelstein
Aug 13, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ya-Fei XuLeonard Petrucelli
Aug 26, 2010·Proceedings of the National Academy of Sciences of the United States of America·Xiu ShanPhilip C Wong
Dec 7, 2010·The EMBO Journal·Youhna M AyalaFrancisco E Baralle
Dec 24, 2010·Nucleic Acids Research·Kee K KimSachiyo Kawamoto
Jan 6, 2011·The Journal of Clinical Investigation·Lionel M IgazVirginia M-Y Lee
Mar 2, 2011·Nature Neuroscience·James R TollerveyJernej Ule
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Jul 26, 2011·Trends in Molecular Medicine·Todd J CohenJohn Q Trojanowski
Nov 16, 2011·The Journal of Experimental Medicine·Vivek SwarupJean-Pierre Julien
Dec 1, 2011·Nature Reviews. Neuroscience·Edward B LeeJohn Q Trojanowski
Dec 14, 2011·The Journal of Clinical Investigation·Cao HuangXu-Gang Xia
Jan 19, 2012·Brain : a Journal of Neurology·Azusa UchidaTakanori Yokota
Feb 11, 2012·Proceedings of the National Academy of Sciences of the United States of America·Yukio Kawahara, Ai Mieda-Sato
Jun 16, 2012·Molecular Neurodegeneration·Zuo-Shang Xu
Oct 2, 2012·Nature Neuroscience·Clotilde Lagier-TourenneGene W Yeo
Dec 14, 2012·The Journal of Biological Chemistry·Shoji WatanabeKoji Yamanaka
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Eveline S ArnoldDon W Cleveland
Feb 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Andrea SerioSiddharthan Chandran
May 10, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ling WengXiao-Jiang Li

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Citations

Feb 28, 2019·Acta Neuropathologica·Peng YinXiao-Jiang Li
Oct 5, 2019·Aging Clinical and Experimental Research·Giuseppe BiamontiClaudia Ghigna
Sep 8, 2017·Acta Neuropathologica Communications·Ahmed YousefJohn Q Trojanowski
Jul 18, 2018·Journal of Central Nervous System Disease·Aino Vesikansa
Dec 24, 2019·Frontiers in Neuroscience·Rita MejziniP Anthony Akkari
Sep 2, 2017·Frontiers in Cellular Neuroscience·Alyssa N CoyneDaniela C Zarnescu
Apr 30, 2019·Frontiers in Neuroscience·Britt A Berning, Adam K Walker
Oct 2, 2020·International Journal of Molecular Sciences·Yee Wa LimMihwa Lee
Dec 29, 2020·Frontiers in Cellular Neuroscience·Santiago E CharifLionel M Igaz
Mar 28, 2021·Journal of Molecular Biology·Shailendra DhakalVijayaraghavan Rangachari
May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea
May 21, 2021·Molecular and Cellular Neurosciences·Rachel A K AtkinsonAnna E King
Aug 8, 2021·Experimental Neurology·Peng YinXiao-Jiang Li
Nov 18, 2021·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration

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Methods Mentioned

BETA
transgenic
PCR
of
pull down
pull-down
pulldown
co-immunoprecipitation
immunoprecipitation
transfection
Co-IP

Software Mentioned

Excel
Scion Image
NeuronJ plugin

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