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C9orf72 nucleotide repeat structures initiate molecular cascades of disease

2014; Nature Portfolio; Volume: 507; Issue: 7491 Linguagem: Inglês

10.1038/nature13124

1476-4687

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,

RNA Research and Splicing

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. Structurally polymorphic C9orf72 hexanucleotide repeats cause an impairment in transcriptional processivity and lead to accumulation of truncated repeat-containing transcripts that bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner resulting in nucleolar stress and C9orf72-linked pathology in amyotrophic lateral sclerosis and frontotemporal dementia. Repeat expansions — mutations in which extra copies of tandemly repeated DNA sequence are generated — underlie more than 40 genetic diseases, which typically lead to neurological and neuromuscular problems. The C9orf72 hexanucleotide repeat expansion has been identified as a cause for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Normal C9orf72 contains up to 25 repeats, whereas those in afflicted individuals can have thousands. This study suggests that a gain in RNA toxicity underlies C9orf72-linked pathology in ALS/FTD. Transcribed C9orf72 hexanucleotide repeats are shown to bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner; as a result nucleolin is mislocalized and functionally impaired, leading to nucleolar stress.