Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients

Hum Mol Genet. 2017 Sep 1;26(17):3421-3431. doi: 10.1093/hmg/ddx233.


Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD.

Publication types

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

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics
  • Autopsy
  • Brain / metabolism
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism
  • Case-Control Studies
  • DNA Repeat Expansion / genetics
  • Female
  • Frontal Lobe / metabolism
  • Frontotemporal Lobar Degeneration / genetics
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neurodegenerative Diseases / genetics
  • RNA Polymerase II
  • Repetitive Sequences, Nucleic Acid / genetics
  • Sequence Analysis, RNA
  • Transcriptional Activation


  • C9orf72 Protein
  • C9orf72 protein, human
  • RNA Polymerase II

Supplementary concepts

  • Amyotrophic lateral sclerosis 1