GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

In this laboratory study using fruit flies, a repeated stretch of DNA in the C9orf72 gene caused nerve damage and problems with the nuclear pore complex and RNA export. This identifies possible mechanisms and genetic modifiers for C9orf72-related ALS and frontotemporal dementia, but it is animal research and not a treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nature14974
• PubMed: 26308899
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{freibaum2015-26308899,
  author  = {Freibaum, B. D. and Lu, Y. and Lopez-Gonzalez, R. and Kim, N. C. and Almeida, S. and Lee, K. H. and Badders, N. and Valentine, M. and others},
  title   = {{GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport}},
  journal = {Nature},
  year    = {2015},
  doi     = {10.1038/nature14974},
  pmid    = {26308899},
  url     = {https://doi.org/10.1038/nature14974}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins Science (New York, N.Y.) · 2014-08-07 · usefulness score 58/100 · Lewy body dementia
• Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS Neuron · 2013-02-12 · usefulness score 57/100 · Lewy body dementia
• Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS Acta neuropathologica · 2013-10-16 · usefulness score 56/100 · Lewy body dementia
• Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion Science translational medicine · 2013-10-01 · usefulness score 53/100 · Lewy body dementia
• Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death Neuron · 2014-12-01 · usefulness score 52/100 · Lewy body dementia

Later studies that cite this one

17 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins Nature neuroscience · 2016-03-21 · usefulness score 58/100 · Brain tissue and pathology
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia
• C9orf72 is required for proper macrophage and microglial function in mice Science (New York, N.Y.) · 2016-03-01 · usefulness score 56/100 · Lewy body dementia
• Stress Granule Assembly Disrupts Nucleocytoplasmic Transport Cell · 2018-04-05 · usefulness score 55/100 · Lewy body dementia
• C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles Cell · 2016-10-01 · usefulness score 54/100 · Lewy body dementia
• Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs Neuron · 2016-04-21 · usefulness score 54/100 · Lewy body dementia

Related studies in Lewy body dementia

• Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS Nature neuroscience · 2015-09-01 · usefulness score 59/100
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100
• A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study The Lancet. Neurology · 2011-12-07 · usefulness score 61/100
• Molecular mechanisms underlying nucleotide repeat expansion disorders Nature reviews. Molecular cell biology · 2021-06-17 · usefulness score 53/100
• Repeat expansion diseases Handbook of clinical neurology · 2018-01-01 · usefulness score 49/100
• RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention Neuron · 2013-10-01 · usefulness score 57/100

Similar studies

• Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia 2013 · Clinical safety
• Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 2012 · Getting a diagnosis
• C9orf72 nucleotide repeat structures initiate molecular cascades of disease 2014 · Lewy body dementia
• C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk 2025 · Inflammation and the immune system
• Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins 2013 · Lewy body dementia
• Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers 2015 · Caregiving

More on Lewy body dementia

• A review that covers this ground C9orf72-mediated ALS and FTD: multiple pathways to disease Nature reviews. Neurology · 2018-09-01 · usefulness score 52/100
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