Title | C9orf72 nucleotide repeat structures initiate molecular cascades of disease. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Haeusler, AR, Donnelly, CJ, Periz, G, Simko, EAJ, Shaw, PG, Kim, M-S, Maragakis, NJ, Troncoso, JC, Pandey, A, Sattler, R, Rothstein, JD, Wang, J |
Journal | Nature |
Volume | 507 |
Issue | 7491 |
Pagination | 195-200 |
Date Published | 2014 Mar 13 |
ISSN | 1476-4687 |
Keywords | Amyotrophic Lateral Sclerosis, B-Lymphocytes, Base Sequence, Cell Nucleolus, DNA, DNA Repeat Expansion, Frontotemporal Dementia, G-Quadruplexes, HEK293 Cells, Humans, Models, Molecular, Neurons, Open Reading Frames, Phosphoproteins, Ribonucleoproteins, RNA, RNA-Binding Proteins, Stress, Physiological, Transcription, Genetic |
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. |
DOI | 10.1038/nature13124 |
Alternate Journal | Nature |
PubMed ID | 24598541 |
PubMed Central ID | PMC4046618 |
Grant List | 5T32CA009110-36 / CA / NCI NIH HHS / United States NS07432 / NS / NINDS NIH HHS / United States NS085207 / NS / NINDS NIH HHS / United States P30 DK089502 / DK / NIDDK NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States P50AG05146 / AG / NIA NIH HHS / United States R01 NS074324 / NS / NINDS NIH HHS / United States R01 NS085207 / NS / NINDS NIH HHS / United States T32 CA009110 / CA / NCI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States |