Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

The EMBO Journal
Pietro FrattaAbraham Acevedo-Arozena

Abstract

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different ...Continue Reading

References

Feb 19, 2002·Nature Genetics·Emma L CoghillSteve D M Brown
Sep 6, 2005·Biochemical and Biophysical Research Communications·Yoshiyuki SakurabaYoichi Gondo
Mar 1, 2008·Science·Jemeen SreedharanChristopher E Shaw
Oct 25, 2008·Annual Review of Genomics and Human Genetics·Abraham Acevedo-ArozenaSteve D M Brown
Jun 9, 2009·Methods in Molecular Biology·Wendy J K Gardiner, Lydia Teboul
Dec 17, 2009·Genesis : the Journal of Genetics and Development·Lien-Szu WuC-K James Shen
Dec 31, 2009·The Journal of Biological Chemistry·Chantelle F SephtonGang Yu
Mar 4, 2010·Acta Neuropathologica·Brian C KraemerGerard D Schellenberg
Jul 6, 2010·Nature Structural & Molecular Biology·Julian KönigJernej Ule
Jul 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Po-Min ChiangPhilip C Wong
Sep 25, 2010·Lancet Neurology·Ian Ra MackenzieManuela Neumann
Oct 30, 2010·Experimental Animals·Yoichi GondoShigeru Makino
Dec 7, 2010·The EMBO Journal·Youhna M AyalaFrancisco E Baralle
Mar 2, 2011·Nature Neuroscience·James R TollerveyJernej Ule
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Eveline S ArnoldDon W Cleveland
Mar 2, 2013·Brain : a Journal of Neurology·Yohei IguchiGen Sobue
Aug 13, 2013·Neuron·Shuo-Chien LingDon W Cleveland
Nov 5, 2013·Methods : a Companion to Methods in Enzymology·Ina HuppertzJernej Ule
Mar 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Chunxing YangZuoshang Xu
Dec 4, 2014·Human Molecular Genetics·Peter I JoyceAbraham Acevedo-Arozena
Aug 8, 2015·Science·Jonathan P LingPhilip C Wong
Nov 26, 2015·Human Molecular Genetics·Peter I JoyceAbraham Acevedo-Arozena
Mar 27, 2016·Journal of Neurochemistry·Antonia Ratti, Emanuele Buratti
Apr 2, 2017·Methods : a Companion to Methods in Enzymology·Joffrey MiannéLydia Teboul
Apr 6, 2017·FEBS Letters·Helena Ederle, Dorothee Dormann
May 28, 2017·BMC Medical Genomics·Jack HumphreyVincent Plagnol
Oct 21, 2017·Brain : a Journal of Neurology·Anny DevoyElizabeth M C Fisher

❮ Previous
Next ❯

Citations

Oct 27, 2018·Brain : a Journal of Neurology·Martine TétreaultChristine Vande Velde
Oct 27, 2018·Brain : a Journal of Neurology·Prasanth SivakumarPietro Fratta
Oct 30, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Peter E A AshBenjamin Wolozin
Oct 26, 2018·Neuropathology and Applied Neurobiology·M Neumann, I R A Mackenzie
Dec 26, 2018·Neuropathology and Applied Neurobiology·D A SolomonS Mizielinska
Feb 12, 2019·PLoS Pathogens·Katsuhisa MasakiRaymond P Roos
Apr 24, 2019·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Sudhanshu P RaikwarAsgar Zaheer
May 18, 2018·The EMBO Journal·Caroline RouauxLuc Dupuis
Jun 26, 2020·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Caterina BendottiEttore Beghi
May 24, 2019·Science Translational Medicine·Elizabeth M C Fisher, David M Bannerman
Jun 27, 2019·Nature Structural & Molecular Biology·Qin CaoDavid S Eisenberg
Sep 27, 2019·Acta Neuropathologica·Ito KawakamiMasato Hasegawa
Jan 11, 2020·Frontiers in Molecular Neuroscience·Liberty François-MoutalMay Khanna
Jan 23, 2020·Acta Neuropathologica Communications·Shih-Ling HuangChe-Kun James Shen
Apr 25, 2019·Nature Communications·Fei ZhuThomas J Cunningham
Jun 17, 2019·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Remya R NairElizabeth M C Fisher
Aug 5, 2020·Acta Neuropathologica·Alexander BamptonAriana Gatt
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
Jul 3, 2020·BMC Bioinformatics·Stefan NieblerBertil Schmidt
Jan 31, 2020·Frontiers in Molecular Biosciences·Suvithanandhini LoganathanDaniela C Zarnescu
Mar 3, 2020·Frontiers in Neuroscience·Yevgeniya A AbramzonRuth Chia
Jan 11, 2019·Disease Models & Mechanisms·Francesca De GiorgioAbraham Acevedo-Arozena
Mar 29, 2019·Genome Biology·Avi SrivastavaRob Patro
Jun 18, 2020·Frontiers in Molecular Neuroscience·Yuan Chao XueHonglin Luo
May 3, 2020·Brain : a Journal of Neurology·Xue ZhangYichang Jia
Oct 17, 2018·Neural Regeneration Research·Jessica R MorriceChristopher A Shaw
Aug 14, 2020·The Journal of Clinical Investigation·Mercedes PrudencioLeonard Petrucelli
Dec 10, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Rubia M MartinKurt C Marsden
Dec 21, 2020·Cellular and Molecular Life Sciences : CMLS·Reem Abouward, Giampietro Schiavo
Oct 11, 2020·Experimental Neurology·Kirsten SieverdingJochen H Weishaupt
Nov 13, 2020·Journal of Neurology, Neurosurgery, and Psychiatry·Eva Maria Johanna de BoerSteve Vucic
Dec 18, 2020·Frontiers in Cellular Neuroscience·Luke McAlaryNeil R Cashman
May 1, 2020·Trends in Neurosciences·Justin J YerburyLuke McAlary
Mar 4, 2021·Nature Reviews. Neuroscience·Paraskevi TziortzoudaFrank Hirth
Nov 7, 2020·Scientific Reports·Jodie WatkinsJemeen Sreedharan
Apr 10, 2021·Trends in Neurosciences·Joseph R KlimKevin Eggan
May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea

❮ Previous
Next ❯

Datasets Mentioned

BETA
SRP133158

Methods Mentioned

BETA
iCLIP
PCR
transgenic
genotyping
biopsies
CLIP
Protein Assay
electrophoresis
biopsy

Software Mentioned

Scope
Tardbp
PhyloP
GENCODE
shRNA
DEXSeq

Related Concepts

Related Feeds

ALS: Phenotypes

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized phenotypically by progressive muscle weakness. Clinical phenotypes of ALS can be classified based on the pattern, level, and area of onset (e.g. bulbar, cervical, lumbar). Here is the latest research investigating phenotypes of ALS.

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.

ALS: Genetics

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating genetic alterations in this genetically heterogeneous disorder.

ALS: Pathogenic Mechanisms

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating pathogenic mechanisms that underlie this genetically heterogeneous disorder.

Researcher Network:CZI Neurodegeneration Challenge

The Neurodegeneration Challenge Network aims to provide funding for and to bring together researchers studying neurodegenerative diseases. Find the latest research from the NDCN grantees here.

ALS: Genetics

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by muscle weakness. ALS is a genetically heterogeneous disorder with several causative genes. Here are the latest discoveries pertaining to the genetics of this disease.

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.

Related Papers

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases
Esther VerstraeteMarcel M Verbeek
© 2022 Meta ULC. All rights reserved