TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD

Science. 2015 Aug 7;349(6248):650-5. doi: 10.1126/science.aab0983.

Abstract

Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Autophagy-Related Proteins
  • Base Sequence
  • Cells, Cultured
  • Cysteine Endopeptidases / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Embryonic Stem Cells
  • Exons / genetics*
  • Frontotemporal Dementia / genetics*
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Isoforms / genetics
  • RNA Splicing*
  • RNA Stability
  • RNA, Messenger / metabolism
  • Sequence Analysis, DNA

Substances

  • Autophagy-Related Proteins
  • DNA-Binding Proteins
  • Protein Isoforms
  • RNA, Messenger
  • TARDBP protein, human
  • TDP-43 protein, mouse
  • ATG4B protein, human
  • Cysteine Endopeptidases

Associated data

  • SRA/SRP057819
  • SRA/SRP057948