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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, Erin G
  • Fagegaltier, Delphine
  • Agius, Phaedra
  • Davis-Porada, Julia
  • Gregory, James
  • Hubbard, Isabel
  • Kang, Kristy
  • Kim, Duyang
  • New York Genome Center ALS Consortium
  • Phatnani, Hemali
  • Kwan, Justin
  • Sareen, Dhruv
  • Broach, James R
  • Simmons, Zachary
  • Arcila-Londono, Ximena
  • Lee, Edward B
  • Van Deerlin, Vivianna M
  • Shneider, Neil A
  • Fraenkel, Ernest
  • Ostrow, Lyle W
  • Baas, Frank
  • Zaitlen, Noah
  • Berry, James D
  • Malaspina, Andrea
  • Fratta, Pietro
  • Cox, Gregory A
  • Thompson, Leslie M
  • Finkbeiner, Steve
  • Dardiotis, Efthimios
  • Miller, Timothy M
  • Chandran, Siddharthan
  • Pal, Suvankar
  • Hornstein, Eran
  • MacGowan, Daniel J
  • Heiman-Patterson, Terry
  • Hammell, Molly G
  • Patsopoulos, Nikolaos A
  • Dubnau, Joshua
  • Nath, Avindra
  • Phatnani, Hemali
  • Shneider, Neil A
  • Manley, James L
  • et al.

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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