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Nature. 2014 Mar 13;507(7491):195-200. doi: 10.1038/nature13124. Epub 2014 Mar 5.

C9orf72 nucleotide repeat structures initiate molecular cascades of disease.

Author information

1
1] Department of Biochemistry and Molecular Biology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA.
2
1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
3
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
4
Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA.
5
Department of Pathology, Johns Hopkins University Baltimore, Maryland, 21205, USA.
6
1] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [3] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.

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.

PMID:
24598541
PMCID:
PMC4046618
DOI:
10.1038/nature13124
[Indexed for MEDLINE]
Free PMC Article

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