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Open Access Publications from the University of California

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

  • Author(s): Conlon, EG
  • Fagegaltier, D
  • Agius, P
  • Davis-Porada, J
  • Gregory, J
  • Hubbard, I
  • Kang, K
  • Kim, D
  • Phatnani, H
  • Shneider, NA
  • Manley, JL
  • Kwan, J
  • Sareen, D
  • Broach, JR
  • Simmons, Z
  • Arcila-Londono, X
  • Lee, EB
  • Van Deerlin, VM
  • Fraenkel, E
  • Ostrow, LW
  • Baas, F
  • Zaitlen, N
  • Berry, JD
  • Malaspina, A
  • Fratta, P
  • Cox, GA
  • Thompson, LM
  • Finkbeiner, S
  • Dardiotis, E
  • Miller, TM
  • Chandran, S
  • Pal, S
  • Hornstein, E
  • Macgowan, DJ
  • Heiman-Patterson, T
  • Hammell, MG
  • Patsopoulos, NA
  • Dubnau, J
  • Nath, A
  • et al.

© 2018, eLife Sciences Publications Ltd. All rights reserved. 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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