Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity

Science. 2019 Feb 15;363(6428):eaav2606. doi: 10.1126/science.aav2606.


How hexanucleotide GGGGCC (G4C2) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2 repeats. The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Brain / metabolism
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / metabolism
  • Dipeptides / genetics
  • Dipeptides / metabolism*
  • Disease Models, Animal
  • Green Fluorescent Proteins
  • HEK293 Cells
  • Heterochromatin / pathology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Lamina / pathology
  • RNA, Double-Stranded / metabolism*
  • Repetitive Sequences, Nucleic Acid


  • C9orf72 Protein
  • C9orf72 protein, human
  • CBX5 protein, human
  • Chromosomal Proteins, Non-Histone
  • Dipeptides
  • Heterochromatin
  • RNA, Double-Stranded
  • Chromobox Protein Homolog 5
  • Green Fluorescent Proteins
  • prolylarginine