C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Nature. 2014 Mar 13;507(7491):195-200. doi: 10.1038/nature13124. Epub 2014 Mar 5.


A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • B-Lymphocytes
  • Base Sequence
  • Cell Nucleolus / genetics
  • Cell Nucleolus / pathology
  • DNA / genetics
  • DNA / metabolism
  • DNA Repeat Expansion / genetics*
  • Frontotemporal Dementia / genetics
  • G-Quadruplexes
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Neurons
  • Nucleolin
  • Open Reading Frames / genetics*
  • Phosphoproteins / metabolism
  • RNA / biosynthesis
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism
  • RNA-Binding Proteins / metabolism
  • Ribonucleoproteins / metabolism
  • Stress, Physiological
  • Transcription, Genetic / genetics


  • Phosphoproteins
  • RNA-Binding Proteins
  • Ribonucleoproteins
  • RNA
  • DNA