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

Ching Chieh Chou, Yi Zhang, Mfon E. Umoh, Spencer W. Vaughan, Ileana Lorenzini, Feilin Liu, Melissa Sayegh, Paul G. Donlin-Asp, Yu Han Chen, Duc M. Duong, Nicholas T. Seyfried, Maureen A. Powers, Thomas Kukar, Chadwick M. Hales, Marla Gearing, Nigel J. Cairns, Kevin B. Boylan, Dennis W. Dickson, Rosa Rademakers, Yong Jie ZhangLeonard Petrucelli, Rita Sattler, Daniela C Zarnescu, Jonathan D. Glass, Wilfried Rossoll

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalNature Neuroscience
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2018

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Nuclear Pore
Cell Nucleus Active Transport
DNA-Binding Proteins
Pathology
Nuclear Pore Complex Proteins
Neurons
Nuclear RNA
Induced Pluripotent Stem Cells
Biotin
Nuclear Proteins
Detergents
Fibroblasts
Frontotemporal Dementia With Motor Neuron Disease
Mutation
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chou, C. C., Zhang, Y., Umoh, M. E., Vaughan, S. W., Lorenzini, I., Liu, F., ... Rossoll, W. (2018). TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nature Neuroscience, 21(2), 228-239. https://doi.org/10.1038/s41593-017-0047-3

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. / Chou, Ching Chieh; Zhang, Yi; Umoh, Mfon E.; Vaughan, Spencer W.; Lorenzini, Ileana; Liu, Feilin; Sayegh, Melissa; Donlin-Asp, Paul G.; Chen, Yu Han; Duong, Duc M.; Seyfried, Nicholas T.; Powers, Maureen A.; Kukar, Thomas; Hales, Chadwick M.; Gearing, Marla; Cairns, Nigel J.; Boylan, Kevin B.; Dickson, Dennis W.; Rademakers, Rosa; Zhang, Yong Jie; Petrucelli, Leonard; Sattler, Rita; Zarnescu, Daniela C; Glass, Jonathan D.; Rossoll, Wilfried.

In: Nature Neuroscience, Vol. 21, No. 2, 01.02.2018, p. 228-239.

Research output: Contribution to journalArticle

Chou, CC, Zhang, Y, Umoh, ME, Vaughan, SW, Lorenzini, I, Liu, F, Sayegh, M, Donlin-Asp, PG, Chen, YH, Duong, DM, Seyfried, NT, Powers, MA, Kukar, T, Hales, CM, Gearing, M, Cairns, NJ, Boylan, KB, Dickson, DW, Rademakers, R, Zhang, YJ, Petrucelli, L, Sattler, R, Zarnescu, DC, Glass, JD & Rossoll, W 2018, 'TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD', Nature Neuroscience, vol. 21, no. 2, pp. 228-239. https://doi.org/10.1038/s41593-017-0047-3
Chou, Ching Chieh ; Zhang, Yi ; Umoh, Mfon E. ; Vaughan, Spencer W. ; Lorenzini, Ileana ; Liu, Feilin ; Sayegh, Melissa ; Donlin-Asp, Paul G. ; Chen, Yu Han ; Duong, Duc M. ; Seyfried, Nicholas T. ; Powers, Maureen A. ; Kukar, Thomas ; Hales, Chadwick M. ; Gearing, Marla ; Cairns, Nigel J. ; Boylan, Kevin B. ; Dickson, Dennis W. ; Rademakers, Rosa ; Zhang, Yong Jie ; Petrucelli, Leonard ; Sattler, Rita ; Zarnescu, Daniela C ; Glass, Jonathan D. ; Rossoll, Wilfried. / TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. In: Nature Neuroscience. 2018 ; Vol. 21, No. 2. pp. 228-239.
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