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

Elife. 2018 Jul 13;7:e37754. doi: 10.7554/eLife.37754.

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.

Keywords: RNA binding proteins; amyotrophic lateral aclerosis; biochemistry; chemical biology; frontotemporal dementia; human; human biology; mRNA splicing; medicine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Brain / pathology
  • C9orf72 Protein / genetics*
  • DNA-Binding Proteins / analysis
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / pathology*
  • Heterogeneous-Nuclear Ribonucleoproteins / analysis*
  • Humans
  • Mutagenesis, Insertional
  • Polypyrimidine Tract-Binding Protein / analysis*
  • RNA Splicing*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • PTBP1 protein, human
  • TARDBP protein, human
  • Polypyrimidine Tract-Binding Protein