C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Article

关键词: AMYOTROPHIC-LATERAL-SCLEROSIS;    RNA G-QUADRUPLEX;    FRONTOTEMPORAL DEMENTIA;    HEXANUCLEOTIDE REPEAT;    GGGGCC REPEAT;    DNA REPEATS;    EXPANSION;    PROTEIN;    ALS;    ACIDS;   

DOI  :  10.1038/nature13124

来源: SCIE

【 摘 要 】

A hexanucleotide repeat expansion (HRE), (GGGGCC)(n), inC9orf72 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.

【 授权许可】

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