C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Aaron R. Haeusler, Christopher J. Donnelly, Goran Periz, Eric A.J. Simko, Patrick G. Shaw, Min Sik Kim, Nicholas J. Maragakis, Juan C. Troncoso, Akhilesh Pandey, Rita Sattler, Jeffrey D. Rothstein, Jiou Wang

Research output: Contribution to journalArticlepeer-review

522 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)195-200
Number of pages6
Issue number7491
StatePublished - 2014

ASJC Scopus subject areas

  • General


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