C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Aaron R. Haeusler, 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.
Christopher J. Donnelly, 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
Goran Periz, 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.
Eric A. Simko, 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.
Patrick G. Shaw, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
Min-Sik Kim, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
Nicholas J. Maragakis, Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA.
Juan C. Troncoso, Department of Pathology, Johns Hopkins University Baltimore, Maryland, 21205, USA.
Akhilesh Pandey, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
Rita Sattler, 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
Jeffrey D. Rothstein, 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.
Jiou Wang, 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.

Document Type

Article

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.

Medical Subject Headings

Amyotrophic Lateral Sclerosis (genetics); B-Lymphocytes; Base Sequence; Cell Nucleolus (genetics, pathology); DNA (genetics, metabolism); DNA Repeat Expansion (genetics); Frontotemporal Dementia (genetics); G-Quadruplexes; HEK293 Cells; Humans; Models, Molecular; Neurons; Open Reading Frames (genetics); Phosphoproteins (metabolism); RNA (biosynthesis, chemistry, genetics, metabolism); RNA-Binding Proteins (metabolism); Ribonucleoproteins (metabolism); Stress, Physiological; Transcription, Genetic (genetics)

Publication Date

3-13-2014

Publication Title

Nature

E-ISSN

1476-4687

Volume

507

Issue

7491

First Page

195

Last Page

200

PubMed ID

24598541

Digital Object Identifier (DOI)

10.1038/nature13124

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