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Cited by 156Amyotrophic Lateral Sclerosis ResearchNuclear Structure and FunctionGenetic Neurodegenerative Diseases

G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD

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Coyne, Alyssa N., Zaepfel, Benjamin L., Hayes, Lindsey, Fitchman, Boris, Salzberg, Yuval, Luo, En-Ching, Bowen, Kelly, Trost, Hannah +7 more·2020·Neuron
DOI 10.1016/j.neuron.2020.06.027PMC PMC8077944
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Abstract

Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.

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  • Genetic screens in ALS model systems have repeatedly uncovered nuclear pore and nucleocytoplasmic transport factors as potent disease modifiers.

    “Genetic screens in ALS model systems have repeatedly uncovered nuclear pore and nucleocytoplasmic transport factors as potent disease modifiers, confirming the significance of these pathways in disease pathogenesis (9–11).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [9]

    The Introduction (page not provided) reports nucleocytoplasmic-transport defects in several C9orf72 ALS/FTD models, and the Results (page not provided) show that manipulating the nucleoporin POM121 changes transport-related defects and neuronal survival. The paper does not report genetic screens repeatedly identifying nuclear-pore and transport factors as disease modifiers, so that specific characterization is not supported by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Disruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture have likewise been described in ALS/FTLD-TDP samples and disease models.

    “Disruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture — all of which we observed upon NLK overexpression — have likewise been described in ALS/FTLD-TDP samples and disease models (9–11, 50).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [9]

    The Results report Ran GTPase mislocalization after POM121 knockdown, and the Discussion describes earlier reports of nuclear pore protein mislocalization in disease models. But this paper's electron-microscopy Results find no overt change in nuclear pore architecture in C9orf72 patient-derived neurons; it also reports reduced nuclear nucleoporins without corresponding cytoplasmic mislocalization. The claim therefore overstates what this source shows, particularly for pore architecture. (LLM, conf=0.88)

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Authors
Coyne, A. N., Zaepfel, B. L., Hayes, L., Fitchman, B., Salzberg, Y., Luo, E.-C., Bowen, K., Trost, H., Aigner, S., Rigo, F., Yeo, G. W., Harel, A., Svendsen, C. N., Sareen, D., & Rothstein, J. D.
Affiliations
  • Johns Hopkins University (US)
  • Bar-Ilan University (IL)
  • University of California San Diego (US)
  • Cedars-Sinai Medical Center (US)
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
Rothstein, Jeffrey D.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2020-09
Volume
107
Issue
6
Pages
1124-1140.e11
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2020.06.027
PMC
PMC8077944
OpenAlex
W3043174733
Cited by
156
References
7
Citations by year
2026: 22 · 2025: 30 · 2024: 31 · 2023: 14 · 2022: 27 · 2021: 28 · 2020: 4
FWCI
7.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Robert Packard Center for ALS Research, Johns Hopkins University
  • Muscular Dystrophy Association
  • Amyotrophic Lateral Sclerosis Association
  • National Institutes of Health
  • Chan Zuckerberg Initiative
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
C9orf72, ALS-FTD, POM121, nucleoporins, nuclear pore complex, nuclear transport, Ran GTPase, iPSC-derived neurons, neurotoxicity, super-resolution structured illumination microscopy
MeSH terms
C9orf72 Protein, Amyotrophic Lateral Sclerosis, Cells, Cultured, Humans, Membrane Glycoproteins, Active Transport, Cell Nucleus, Nuclear Pore, Nuclear Pore Complex Proteins, Induced Pluripotent Stem Cells, Frontotemporal Dementia, HEK293 Cells, Neural Stem Cells

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