TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

Topic: Brain proteins, microglia and lab models

The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

Key findings

• However, the composition of aggregates and their contribution to the disease process remain unknown.
• Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery.
• Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons.
• Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72.
• Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

Why it matters

TDP-43 aggregates were found to be enriched for nuclear pore and transport components, and mutant TDP-43 interfered with nuclear import and RNA export in neurons and patient-derived cells. This is laboratory and tissue work implicating transport defects in ALS/FTD, with no treatment tested.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41593-017-0047-3
• PubMed: 29311743
• Original source →
• Free full text: Nature Neuroscience →

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

@article{chou2018-29311743,
  author  = {Chou, C. C. and Zhang, Y. and Umoh, M. E. and Vaughan, S. W. and Lorenzini, I. and Liu, F. and Sayegh, M. and Donlin-Asp, P. G. and others},
  title   = {{TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD}},
  journal = {Nature neuroscience},
  year    = {2018},
  doi     = {10.1038/s41593-017-0047-3},
  pmid    = {29311743},
  url     = {https://doi.org/10.1038/s41593-017-0047-3}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 14.

• TDP-43 pathology, cognitive decline, and dementia in old age JAMA neurology · 2013-11-01 · usefulness score 64/100 · Brain tissue and pathology
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · 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 · Lewy body dementia
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 58/100 · 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
• RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention Neuron · 2013-10-01 · usefulness score 57/100 · Lewy body dementia
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia
• Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization Cell · 2015-09-01 · usefulness score 56/100 · Lewy body dementia
• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations Neuron · 2014-02-01 · 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
• Structural determinants of the cellular localization and shuttling of TDP-43 Journal of cell science · 2008-10-28 · usefulness score 51/100 · Lewy body dementia

Later studies that cite this one

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

• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · 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
• Stress granules and neurodegeneration Nature reviews. Neuroscience · 2019-10-03 · usefulness score 55/100 · Lewy body dementia
• TDP-43 proteinopathies: a new wave of neurodegenerative diseases Journal of neurology, neurosurgery, and psychiatry · 2020-11-11 · usefulness score 54/100 · Lewy body dementia
• C9orf72-mediated ALS and FTD: multiple pathways to disease Nature reviews. Neurology · 2018-09-01 · usefulness score 52/100 · Lewy body dementia
• The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies Experimental & molecular medicine · 2020-10-13 · usefulness score 51/100 · Lewy body dementia
• Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation Nature reviews. Neuroscience · 2021-03-02 · usefulness score 49/100 · Brain tissue and pathology
• FUS and TDP-43 Phases in Health and Disease Trends in biochemical sciences · 2021-01-11 · usefulness score 49/100 · Lewy body dementia

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• Stress Granule Assembly Disrupts Nucleocytoplasmic Transport Cell · 2018-04-05 · usefulness score 55/100
• 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
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100
• TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes Proceedings of the National Academy of Sciences of the United States of America · 2012-02-09 · usefulness score 48/100

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• Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR FEBS Letters · 2025-10-22 · usefulness score 35/100 · Brain tissue and pathology
• The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia Proceedings of the National Academy of Sciences of the United States of America · 2006-10-02 · usefulness score 45/100 · Inflammation and the immune system
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