%0 Journal Article %J Nature %D 2014 %T C9orf72 nucleotide repeat structures initiate molecular cascades of disease. %A Haeusler, Aaron R %A Donnelly, Christopher J %A Periz, Goran %A Simko, Eric A J %A Shaw, Patrick G %A Kim, Min-Sik %A Maragakis, Nicholas J %A Troncoso, Juan C %A Pandey, Akhilesh %A Sattler, Rita %A Rothstein, Jeffrey D %A Wang, Jiou %K Amyotrophic Lateral Sclerosis %K B-Lymphocytes %K Base Sequence %K Cell Nucleolus %K DNA %K DNA Repeat Expansion %K Frontotemporal Dementia %K G-Quadruplexes %K HEK293 Cells %K Humans %K Models, Molecular %K Neurons %K Open Reading Frames %K Phosphoproteins %K Ribonucleoproteins %K RNA %K RNA-Binding Proteins %K Stress, Physiological %K Transcription, Genetic %X

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.

%B Nature %V 507 %P 195-200 %8 2014 Mar 13 %G eng %N 7491 %1 http://www.ncbi.nlm.nih.gov/pubmed/24598541?dopt=Abstract %R 10.1038/nature13124