Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.

ELife
Erin G ConlonJames L Manley

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9' brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.

References

Nov 26, 1998·Acta Neuropathologica·S D GinsbergJ Q Trojanowski
Jun 2, 2001·The New England Journal of Medicine·L P Rowland, N A Shneider
Jul 24, 2004·Nature Medicine·Christopher A Ross, Michelle A Poirier
Aug 12, 2004·FEBS Letters·Yimin Hua, Jianhua Zhou
Aug 18, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Honglai ZhangGary J Bassell
Mar 24, 2009·Cell·Clotilde Lagier-Tourenne, Don W Cleveland
May 29, 2009·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·A AlonsoM A Hernán
Nov 21, 2009·RNA·Jean-François FisetteBenoit Chabot
Jul 14, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shuo-Chien LingDon W Cleveland
Aug 26, 2010·Proceedings of the National Academy of Sciences of the United States of America·Xiu ShanPhilip C Wong
Sep 4, 2010·Cellular Signalling·María Gabriela ThomasGraciela Lidia Boccaccio
Oct 26, 2010·Journal of Neurology, Neurosurgery, and Psychiatry·Harro SeelaarJohn C van Swieten
Nov 6, 2010·The Journal of Biological Chemistry·Chantelle F SephtonGang Yu
Mar 2, 2011·Nature Neuroscience·James R TollerveyJernej Ule
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Jun 12, 2012·Cell·Stephanie C Weber, Clifford P Brangwynne
Oct 2, 2012·Nature Neuroscience·Clotilde Lagier-TourenneGene W Yeo
Dec 21, 2012·EMBO Molecular Medicine·Hitomi TsuijiKoji Yamanaka
Feb 16, 2013·Brain : a Journal of Neurology·Suzanne LesageUNKNOWN French Parkinson’s Disease Genetics Study Group
Jun 7, 2013·Human Molecular Genetics·Tomohiko IshiharaOsamu Onodera
Aug 13, 2013·Neuron·Shuo-Chien LingDon W Cleveland
Nov 26, 2013·Cell Reports·Jacob C SchwartzThomas R Cech
Dec 21, 2013·Trends in Molecular Medicine·Lies Vanden BroeckBart Dermaut
Dec 21, 2013·Acta Neuropathologica·Ian R A MackenzieManuela Neumann
Dec 24, 2013·Neurology·Davina J Hensman MossSarah J Tabrizi
May 9, 2014·Acta Neuropathologica·Elaine Y LiuEdward B Lee
Feb 6, 2015·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Emma L ScotterChristopher E Shaw
May 28, 2015·Proceedings of the National Academy of Sciences of the United States of America·Shana Elbaum-GarfinkleClifford P Brangwynne
Jul 21, 2015·Nature Neuroscience·Mercedes PrudencioLeonard Petrucelli
Aug 8, 2015·Science·Jonathan P LingPhilip C Wong
Sep 4, 2015·Current Protocols in Bioinformatics·Alexander Dobin, Thomas R Gingeras

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Citations

Aug 22, 2018·ELife·Aaron D Gitler, John D Fryer
Dec 24, 2018·Neuropathology and Applied Neurobiology·B BorroniE Buratti
Feb 12, 2019·PLoS Pathogens·Katsuhisa MasakiRaymond P Roos
Oct 27, 2018·Brain : a Journal of Neurology·Martine TétreaultChristine Vande Velde
Jul 4, 2019·Journal of Molecular Neuroscience : MN·Polyxeni StamatiEfthimios Dardiotis
Aug 5, 2020·Acta Neuropathologica·Alexander BamptonAriana Gatt
Nov 7, 2019·Frontiers in Cellular Neuroscience·Jessica BellmannJared Sterneckert
May 21, 2019·Human Molecular Genetics·Ching-On Wong, Kartik Venkatachalam
Aug 7, 2019·Cellular and Molecular Neurobiology·Benedetta PerroneSebastiano Cavallaro
Oct 21, 2020·Essays in Biochemistry·Yu SunGabriel Balmus
Oct 16, 2020·Genome Research·Qingqing WangDonald C Rio
Jun 3, 2021·International Journal of Molecular Sciences·Chisato KinoshitaKoji Aoyama

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Methods Mentioned

BETA
PCR
SMA
co-immunoprecipitation
CLIP
RNA-seq
Co-IP

Software Mentioned

Graphpad for Prism
C9ALS
Gencode
STAR
nonALS
ImageJ
LeafCutter
ImageQuant

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