GGGGCC repeat expansion in C9ORF72 compromises nucleocytoplasmic transport
By Brian D. Freibaum, Yubing Lu, Rodrigo Lopez-Gonzalez, Nam Chul Kim, S. Almeida, Kyung‐Ha Lee, Nisha M. Badders, M. Valentine, B. Miller, Philip C. Wong and 4 more. Nature, 2015
805 citations recorded by the source corpus.
The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.
Subfields: Genetics, Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/cf9b297c1a69093672828f2c4a19387a4bbb3abc
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In Molecular Biology
Citations in the corpus
- RNA Phase Transitions in Repeat Expansion Disorders (2017, neutral): “…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.”
- In vivo aspects of protein folding and quality control (2016, background): “Toxic protein aggregation interferes with nucleocytoplasmic transport of RNA and protein and generally impairs RNA homeostasis (156, 158).”