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

The New York Genome Center ALS Consortium

doi:10.7554/eLife.37754

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

The New York Genome Center ALS Consortium

Stony Brook University

Columbia University
New York Genome Center
University of Maryland, Baltimore
Cedars-Sinai Medical Center
University of California at Los Angeles
Pennsylvania State University
Henry Ford Health System
University of Pennsylvania
Massachusetts Institute of Technology
Johns Hopkins University
Leiden University
University of California at San Francisco
Harvard University
Massachusetts General Hospital
Queen Mary University of London
Mid and South Essex NHS Foundation Trust
University College London Hospitals NHS Foundation Trust
Jackson Laboratory
University of California at Irvine
Gladstone Institutes
University of Thessaly
Washington University St. Louis
University of Edinburgh
Weizmann Institute of Science
Icahn School of Medicine at Mount Sinai
Temple University
Cold Spring Harbor Laboratory
Broad Institute
National Institutes of Health

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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 language	English
Article number	e37754
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.37754
State	Published - Jul 13 2018

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10.7554/eLife.37754

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@article{db4c55de086749ebbbac3d0a9534730a,

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 {\textquoteleft}like-C9{\textquoteright} 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 Broach, \{James R.\} 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 = jul,

day = "13",

doi = "10.7554/eLife.37754",

language = "English",

volume = "7",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

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 R.

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.

UR - https://www.scopus.com/pages/publications/85052201257

U2 - 10.7554/eLife.37754

DO - 10.7554/eLife.37754

M3 - Article

C2 - 30003873

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e37754

ER -

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

Abstract

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