C9orf72 Nucleotide Repeat Structures Initiate Molecular Cascades of Disease

By A. Haeusler, Christopher J. Donnelly, Goran Periz, Eric A J Simko, Patrick G. Shaw, Min-Sik Kim, N. Maragakis, J. Troncoso, Akhilesh Pandey, R. Sattler and 2 more. Nature, 2014

922 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/4c85d11c7ea76b504fd791f95e5eebd2591ee484

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In Molecular Biology

1. D. Rhodes
2. Payal Gupta
3. Rushikesh M Khadake
4. Shounok Panja
5. Krushna Shinde
6. Ambadas B Rode
7. H. Lipps

Citations in the corpus

• G-quadruplexes and their regulatory roles in biology (2015, background): “This led to nucleolar stress and perturbations in RNA processing, initiating a molecular cascade that resulted in a type of a neurodegenerative disorder (44).”
• Alternative RNA Conformations: Companion or Combatant (2022, background): “(b) Intron 1 of the C9ORF72 gene contains a Gquadruplex-forming sequence, sequestering the hnRNPA1 protein and resulting in ALS/FTD. Small molecules that destabilize the G-quadruplex release the hnRNPA1 protein in its free form leading for normal development.”