Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

Acta Neuropathologica
Peng YinXiao-Jiang Li

Abstract

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target.

References

Jan 1, 1992·Experimental Brain Research·C Magariños-AsconeE García-Austt
May 5, 2004·The Journal of Cell Biology·Junichi HitomiMasaya Tohyama
Jun 27, 2007·The American Journal of Pathology·Nigel J CairnsIan R A Mackenzie
Aug 25, 2007·Brain : a Journal of Neurology·Ekaterina V IlievaManuel Portero-Otín
Mar 1, 2008·Science·Jemeen SreedharanChristopher E Shaw
Sep 20, 2008·PLoS Genetics·Nicola J RutherfordRosa Rademakers
Mar 24, 2009·Cell·Clotilde Lagier-Tourenne, Don W Cleveland
Oct 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Iga WegorzewskaRobert H Baloh
Dec 25, 2009·Neurobiology of Aging·Nicola TicozziJohn E Landers
Jan 28, 2010·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Felix GeserJohn Q Trojanowski
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hans WilsSamir Kumar-Singh
Mar 18, 2010·Nature Reviews. Neurology·Alice S Chen-PlotkinJohn Q Trojanowski
Aug 26, 2010·Proceedings of the National Academy of Sciences of the United States of America·Xiu ShanPhilip C Wong
Jan 6, 2011·The Journal of Clinical Investigation·Lionel M IgazVirginia M-Y Lee
Feb 2, 2011·Journal of Pharmacological Sciences·Akiko YamamuroSadaaki Maeda
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Jun 7, 2011·Acta Neuropathologica·Ian R A MackenzieVirginia M Y Lee
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
Jun 16, 2012·Molecular Neurodegeneration·Zuo-Shang Xu
Jul 4, 2012·Journal of Alzheimer's Disease : JAD·Tania F GendronLeonard Petrucelli
Aug 1, 2013·Human Molecular Genetics·Jonathan Janssens, Christine Van Broeckhoven
Dec 27, 2013·Nature Neuroscience·Alan E RentonBryan J Traynor
Jan 2, 2014·Human Molecular Genetics·Sen YanXiao-Jiang Li
Jan 21, 2014·Biochimica Et Biophysica Acta·Giovanni De MarcoAndrea Calvo
Mar 25, 2014·Acta Neuropathologica·Keith A JosephsDennis W Dickson
Sep 7, 2014·Biochimica Et Biophysica Acta·Senda Ajroud-Driss, Teepu Siddique
Nov 12, 2014·Annual Review of Pathology·Scott A Oakes, Feroz R Papa
Jan 30, 2015·Nature Communications·Quan LiYukio Kawahara
May 29, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Weili YangXiao-Jiang Li
Aug 27, 2015·Nature·Ke ZhangJeffrey D Rothstein
Aug 27, 2015·Nature·Brian D FreibaumJ Paul Taylor

❮ Previous
Next ❯

Citations

Mar 17, 2020·The EMBO Journal·Bahram KhosraviDieter Edbauer
Apr 30, 2019·Frontiers in Neuroscience·Britt A Berning, Adam K Walker
Dec 24, 2019·Frontiers in Neuroscience·Rita MejziniP Anthony Akkari
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
Jan 8, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jiasi WuXianli Meng
Dec 29, 2020·Frontiers in Cellular Neuroscience·Santiago E CharifLionel M Igaz
May 1, 2021·Human Molecular Genetics·Chunhui HuangSen Yan
May 21, 2021·IScience·Deepak ChhanganiDiego E Rincon-Limas
Aug 8, 2021·Experimental Neurology·Peng YinXiao-Jiang Li
Sep 20, 2021·Journal of Molecular Biology·Skylar S WrightVijay A Rathinam

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
Protein Assay
transfection
cleavage assay
fluorescence

Software Mentioned

ImageJ
Openlab
Improvision

Related Concepts

Related Feeds

Cell-Type Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

Cell-Type-Specific Viral Vectors (ASM)

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

Basal Ganglia

Basal Ganglia are a group of subcortical nuclei in the brain associated with control of voluntary motor movements, procedural and habit learning, emotion, and cognition. Here is the latest research.

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

Cell-Type-Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

ALS & FTD: TDP-43

TAR DNA-binding protein 43 (TDP-43) is a pathological protein identified in sporadic Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Here are the latest discoveries pertaining to TDP-43 and these diseases.

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.