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
N1 - Publisher Copyright:
© 2018, eLife Sciences Publications Ltd. All rights reserved.
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
C2 - 30003873
AN - SCOPUS:85052201257
SN - 2050-084X
VL - 7
JO - eLife
JF - eLife
M1 - e37754
ER -