C9orf72 nucleotide repeat structures initiate molecular cascades of disease
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)
Digital Object Identifier (DOI)
Haeusler, Aaron R.; Donnelly, Christopher J.; Periz, Goran; Simko, Eric A.; Shaw, Patrick G.; Kim, Min-Sik; Maragakis, Nicholas J.; Troncoso, Juan C.; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D.; and Wang, Jiou, "C9orf72 nucleotide repeat structures initiate molecular cascades of disease" (2014). Translational Neuroscience. 1358.