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

The New York Genome Center ALS Consortium

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere37754
JournaleLife
Volume7
DOIs
StatePublished - Jul 13 2018

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Frontotemporal Dementia
Heterogeneous-Nuclear Ribonucleoprotein Group F-H
Brain
RNA-Binding Proteins
Genes
Defects
Amyotrophic lateral sclerosis 1
Frontotemporal Dementia With Motor Neuron Disease

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

@article{9d26d1866e7a4fb2a40b5dd4e143595a,
title = "Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism",
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.",
author = "{The New York Genome Center ALS Consortium} and Conlon, {Erin G.} and Delphine Fagegaltier and Phaedra Agius and Julia Davis-Porada and James Gregory and Isabel Hubbard and Kristy Kang and Duyang Kim and Hemali Phatnani and Shneider, {Neil A.} and Manley, {James L.} and Justin Kwan and Dhruv Sareen and James Broach and Zachary Simmons and Ximena Arcila-Londono and Lee, {Edward B.} and {Van Deerlin}, {Vivianna M.} and Ernest Fraenkel and Ostrow, {Lyle W.} and Frank Baas and Noah Zaitlen and Berry, {James D.} and Andrea Malaspina and Pietro Fratta and Cox, {Gregory A.} and Thompson, {Leslie M.} and Steve Finkbeiner and Efthimios Dardiotis and Miller, {Timothy M.} and Siddharthan Chandran and Suvankar Pal and Eran Hornstein and Macgowan, {Daniel J.} and Terry Heiman-Patterson and Hammell, {Molly G.} and Patsopoulos, {Nikolaos A.} and Joshua Dubnau and Avindra Nath",
year = "2018",
month = "7",
day = "13",
doi = "10.7554/eLife.37754",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism. / The New York Genome Center ALS Consortium.

In: eLife, Vol. 7, e37754, 13.07.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism

AU - The New York Genome Center ALS Consortium

AU - Conlon, Erin G.

AU - Fagegaltier, Delphine

AU - Agius, Phaedra

AU - Davis-Porada, Julia

AU - Gregory, James

AU - Hubbard, Isabel

AU - Kang, Kristy

AU - Kim, Duyang

AU - Phatnani, Hemali

AU - Shneider, Neil A.

AU - Manley, James L.

AU - Kwan, Justin

AU - Sareen, Dhruv

AU - Broach, James

AU - Simmons, Zachary

AU - Arcila-Londono, Ximena

AU - Lee, Edward B.

AU - Van Deerlin, Vivianna M.

AU - Fraenkel, Ernest

AU - Ostrow, Lyle W.

AU - Baas, Frank

AU - Zaitlen, Noah

AU - Berry, James D.

AU - Malaspina, Andrea

AU - Fratta, Pietro

AU - Cox, Gregory A.

AU - Thompson, Leslie M.

AU - Finkbeiner, Steve

AU - Dardiotis, Efthimios

AU - Miller, Timothy M.

AU - Chandran, Siddharthan

AU - Pal, Suvankar

AU - Hornstein, Eran

AU - Macgowan, Daniel J.

AU - Heiman-Patterson, Terry

AU - Hammell, Molly G.

AU - Patsopoulos, Nikolaos A.

AU - Dubnau, Joshua

AU - Nath, Avindra

PY - 2018/7/13

Y1 - 2018/7/13

N2 - 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.

AB - 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.

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U2 - 10.7554/eLife.37754

DO - 10.7554/eLife.37754

M3 - Article

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JF - eLife

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