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Cited by 836Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesNuclear Structure and Function

ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import

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Dormann, Dorothee, Rodde, Ramona, Edbauer, Dieter, Bentmann, Eva, Fischer, Ingeborg, Hruscha, Alexander, Than, Manuel E, Mackenzie, Ian R A +4 more·2010·The EMBO Journal
DOI 10.1038/emboj.2010.143PMC PMC2924641
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Abstract

Mutations in fused in sarcoma (FUS) are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls, FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD-FUS). We show that a non-classical PY nuclear localization signal (NLS) in the C-terminus of FUS is necessary for nuclear import. The majority of fALS-associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease-causing mutations within a PY-NLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co-deposit with inclusions in fALS and FTLD-FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies.

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  • Reanalysis of Liu et al. data demonstrated a significant upregulation of NLK mRNA in nuclei lacking TDP43.

    “Reanalysis of these data demonstrated a significant upregulation of NLK mRNA in nuclei lacking TDP43 (Figure 7D).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [30]

    The Introduction and Results discuss nuclear transport of FUS and TDP-43, while the Discussion describes Figure 7 in relation to stress-granule markers. Searches for NLK mRNA, Liu et al. data, and TDP-43-negative nuclei found no passage reporting the claimed reanalysis or upregulation. No page numbers were provided in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Direct interaction between NLK and the RanGAP1-RanBP2 complex.

    “We and others noted a direct interaction between NLK and the RanGAP1-RanBP2 complex ((30); see Figure 4), which is critical for maintaining the Ran gradient and nuclear import/export (51).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [30]

    The Results passages describe FUS binding to Transportin and its Transportin-mediated nuclear import, not an interaction between NLK and the RanGAP1–RanBP2 complex. Searches for that interaction and for the complex’s role in maintaining the Ran gradient found no passage addressing either point in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Both RanGAP1 and RanBP2 co-immunoprecipitated with FLAG-NLK in HEK293 cells.

    “Consistent with a previous screen for kinase-interacting proteins (30), both RanGAP1 and RanBP2 co-immunoprecipitated with FLAG-NLK in HEK293 cells (Figure 4A–C).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [30]

    The cited paper’s Results describe Transportin-mediated nuclear import of FUS, including Trp1/2 knockdown (Figure 4), not a kinase-interacting-protein screen. Searches for NLK, RanGAP1, RanBP2, and FLAG-NLK found no passage in our copy reporting the stated co-immunoprecipitation. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Dormann, D., Rodde, R., Edbauer, D., Bentmann, E., Fischer, I., Hruscha, A., Than, M. E., Mackenzie, I. R. A., Capell, A., Schmid, B., Neumann, M., & Haass, C.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • Vancouver General Hospital (CA)
Corresponding author
Haass, Christian
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2010-07-06
Volume
29
Issue
16
Pages
2841-2857
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/emboj.2010.143
PMC
PMC2924641
OpenAlex
W2075186362
Cited by
836
References
1
Citations by year
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FWCI
35.31
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • DZNE Pub (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Stavros Niarchos Foundation
  • Hans und Ilse Breuer-Stiftung
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
FUS mutations, familial ALS, nuclear import, transportin, stress granules, age of onset
MeSH terms
Amino Acid Sequence, Amyotrophic Lateral Sclerosis, Animals, Cells, Cultured, Cytoplasmic Granules, HeLa Cells, Humans, Molecular Sequence Data, Neurons, Zebrafish, Point Mutation, Protein Structure, Tertiary, Active Transport, Cell Nucleus, Karyopherins, RNA-Binding Protein FUS, Gene Knockdown Techniques

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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