Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers

Cell. 2016 Oct 20;167(3):789-802.e12. doi: 10.1016/j.cell.2016.10.003.


Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.

Keywords: 1,6-hexanediol; C9orf72; amyloid-like polymers; cellular puncta not invested by surrounding membranes; intermediate filaments; labile; low complexity sequence polymers; toxic PRn and GRn poly-dipeptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • C9orf72 Protein
  • DNA Repeat Expansion
  • Dipeptides / chemistry
  • Dipeptides / genetics
  • Dipeptides / metabolism*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • HeLa Cells
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Protein Domains
  • Proteins / genetics
  • Proteins / metabolism*


  • C9orf72 Protein
  • C9orf72 protein, human
  • Dipeptides
  • Intermediate Filament Proteins
  • Peptides
  • Proteins
  • polyproline
  • polyarginine