title: C9orf72 nucleotide repeat structures initiate molecular cascades of disease.
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.
authors.affiliation: 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.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Haeusler
authors.affiliation: 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Donnelly
authors.affiliation: 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.
authors.forename: Goran
authors.initials: G
authors.lastname: Periz
authors.affiliation: 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.
authors.forename: Eric A J
authors.initials: EA
authors.lastname: Simko
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Shaw
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Min-Sik
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
authors.affiliation: Department of Pathology, Johns Hopkins University Baltimore, Maryland, 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.affiliation: 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Sattler
authors.affiliation: 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.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.affiliation: 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.
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D001402:B-Lymphocytes; D001483:Base Sequence; D002466:Cell Nucleolus / Q000235:genetics / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics; D054856:G-Quadruplexes; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009474:Neurons; D016366:Open Reading Frames / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic / Q000235:genetics; D000097796:Nucleolin
chemical_list: D004247:DNA; D010750:Phosphoproteins; D012313:RNA; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D000097796:Nucleolin