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 and Jiou Wang ()
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Aaron R. Haeusler: Johns Hopkins University Baltimore
Christopher J. Donnelly: Johns Hopkins University Baltimore
Goran Periz: Johns Hopkins University Baltimore
Eric A. J. Simko: Johns Hopkins University Baltimore
Patrick G. Shaw: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore
Min-Sik Kim: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore
Nicholas J. Maragakis: Johns Hopkins University Baltimore
Juan C. Troncoso: Johns Hopkins University Baltimore
Akhilesh Pandey: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore
Rita Sattler: Johns Hopkins University Baltimore
Jeffrey D. Rothstein: Johns Hopkins University Baltimore
Jiou Wang: Johns Hopkins University Baltimore

Nature, 2014, vol. 507, issue 7491, 195-200

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/nature13124

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