The C9ORF72 repeat expansion disrupts nucleocytoplasmic transport
By Ke Zhang, Christopher J. Donnelly, A. Haeusler, J. Grima, James B. Machamer, Peter Steinwald, E. Daley, Sean J. Miller, Kathleen M. Cunningham, Svetlana Vidensky and 11 more. Nature, 2015
961 citations recorded by the source corpus.
The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Subfields: Genetics, Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/c98c22c7092323f6744c52fa6fc6bd2dd260469c
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Citations in the corpus
- RNA Phase Transitions in Repeat Expansion Disorders (2017, positive): “…and foci formation likely occur upstream of known drivers of cellular toxicity such as sequestration of RNA binding proteins 14 , nucleolar stress 41 and disruption of nucleocytoplasmic transport 42,43 , although a direct link between foci formation and cellular toxicity remains to be established.”
- Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use (2016, background): “In contrast, at least RAN Repeat-Associated non-ATG translation (RAN) is known to be involved in the important expression of all frames of the G-quadruplex forming hexanucleotide expansion of a GGGGCC repeat in what had until recently been considered the 5′ UTR of the mRNA for C9orf72 that is key to”