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Cited by 660Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersRNA Research and Splicing

Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations

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Alami, Nael H., Smith, Rebecca B., Carrasco, Monica A., Williams, Luis A., Winborn, Christina S., Han, Steve S.W., Kiskinis, Evangelos, Winborn, Brett +11 more·2014·Neuron
DOI 10.1016/j.neuron.2013.12.018PMC PMC3939050
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Abstract

The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

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Crossref · 10.1016/j.neuron.2013.12.018

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  • TDP43 is primarily nuclear in healthy cells, in contrast to nuclear exclusion and cytosolic deposition characteristic of ALS.

    “TDP43 is primarily nuclear in healthy cells, in contrast to the nuclear exclusion and cytosolic deposition of TDP43 that are characteristic of ALS (3).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [3]

    The Introduction states that TDP-43 is primarily nuclear and that pathological cytoplasmic inclusions containing it are characteristic of ALS. It does not state that nuclear exclusion is characteristic of ALS; a search for “nuclear exclusion” found no supporting passage. No page number is available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Approximately 50% of individuals with frontotemporal lobar degeneration (FTLD) show TDP43 mislocalization as in ALS.

    “Approximately 50% of individuals with frontotemporal lobar degeneration (FTLD) show TDP43 mislocalization as in ALS(3).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [3]

    The Introduction (page unavailable) describes pathological cytoplasmic TDP-43 inclusions in both FTLD and ALS, supporting the comparison. It does not give a prevalence figure for FTLD, so the claim that approximately 50% of affected individuals show mislocalization is unsupported by this copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Shared genetics underlying both ALS and FTD testify to the close overlap between ALS and FTLD with TDP43 pathology (FTLD-TDP).

    “These observations, as well as shared genetics underlying both ALS and FTD, testify to the close overlap between ALS and FTLD with TDP43 pathology (FTLD-TDP) (3, 45).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [3]

  • Up to half of people with ALS demonstrate cognitive impairment reminiscent of FTLD, while ~1/3 of those with FTLD show motor neuron disease that is indistinguishable from ALS.

    “In addition, up to half of people with ALS demonstrate cognitive impairment reminiscent of FTLD, while ~1/3 of those with FTLD show motor neuron disease that is indistinguishable from ALS (3, 45).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [3]

    The Introduction says TDP-43 is associated with both FTLD and ALS, but it does not address how often people with either condition have symptoms of the other. Searches for cognitive impairment, motor neuron disease, and the claimed proportions found no supporting passage in our copy; pages were not provided. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Authors
Alami, N. H., Smith, R. B., Carrasco, M. A., Williams, L. A., Winborn, C. S., Han, S. S. W., Kiskinis, E., Winborn, B., Freibaum, B. D., Kanagaraj, A., Clare, A. J., Badders, N. M., Bilican, B., Chaum, E., Chandran, S., Shaw, C. E., Eggan, K. C., Maniatis, T., & Taylor, J. P.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Harvard University (US)
  • University of Tennessee Health Science Center (US)
  • MRC Centre for Regenerative Medicine (GB)
  • King's College London (GB)
  • Columbia University Irving Medical Center (US)
Corresponding author
Taylor, J. Paul
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2014-02
Volume
81
Issue
3
Pages
536-543
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2013.12.018
PMC
PMC3939050
OpenAlex
W2154923417
Cited by
660
References
3
Citations by year
2026: 37 · 2025: 56 · 2024: 41 · 2023: 49 · 2022: 41 · 2021: 65 · 2020: 60 · 2019: 58 · 2018: 64 · 2017: 55 · 2016: 60 · 2015: 44 · 2014: 30
FWCI
41.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • David and Lucile Packard Foundation
  • Foundation for the National Institutes of Health
  • Wellcome Trust (089701)
  • Motor Neurone Disease Association (CHANDRAN/MAR10/982-797)
  • Medical Research Council (MC_G1000733)
  • National Institute on Aging (R01AG031587, AG031587)
  • National Cancer Institute (P30CA021765)
  • National Institute of Neurological Disorders and Stroke (R01NS053825, NS053825, DP1NS082099)
  • National Center for Chronic Disease Prevention and Health Promotion (8DP1NS082099)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
TDP-43, amyotrophic lateral sclerosis, mRNA transport, axonal transport, microtubule transport, RNA-binding proteins, TDP-43 mutations, motor neurons, frontotemporal lobar degeneration, cytoplasmic inclusions
MeSH terms
Kruppel-Like Factor 4, Amyotrophic Lateral Sclerosis, Animals, Axonal Transport, Cells, Cultured, Cerebral Cortex, DNA-Binding Proteins, Drosophila, Humans, Luminescent Proteins, Mitochondria, Motor Neurons, Mutation, RNA, Messenger, RNA-Binding Proteins, Drosophila Proteins, Animals, Genetically Modified, Octamer Transcription Factor-3, Mice, Kruppel-Like Transcription Factors, SOXB1 Transcription Factors

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