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 - Funding Information:
This work was supported by NIH grant R35 GM 118136 to JLM. EGC was supported in part by NIH training grant 5T32GM008798. RNA sequencing and related analyses at the NYGC were supported by the ALS Association (grant 15-LGCA-234) and the Tow Foundation, which also provided direct support for the Eleanor and Lou Gehrig ALS Center (NAS). We acknowledge the Target ALS postmortem tissue core, as well as the New York Brain Bank for providing us with human brain samples. We thank Dr. Lawrence Honig of the Taub Institute/ADRC for providing FTD samples. We also thank Aarti Sharma and Beatriz Blanco-Redondo for many helpful discussions that helped shape this study.
Funding Information:
This work was supported by NIH grant R35 GM 118136 to JLM. EGC was supported in part by NIH training grant 5T32GM008798. RNA sequencing and related analyses at the NYGC were supported by the ALS Association (grant 15-LGCA-234) and the Tow Foundation, which also provided direct support for the Eleanor and Lou Gehrig ALS Center (NAS). We acknowledge the Target ALS postmortem tissue core, as well as the New York Brain Bank for providing us with human brain samples. We thank Dr Lawrence Honig of the Taub Institute/ADRC for providing FTD samples. We also thank Aarti Sharma and Beatriz Blanco-Redondo for many helpful discussions that helped shape this study.
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.
UR - http://www.scopus.com/inward/record.url?scp=85052201257&partnerID=8YFLogxK
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 -