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 V Rademakers, Yongjie Zhang & 5 others Leonard Petrucelli, Rita Sattler, Daniela C. Zarnescu, Jonathan D. Glass, Wilfried Rossol

Research output: Contribution to journalArticle

66 Citations (Scopus)

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

Fingerprint

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

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 V; Zhang, Yongjie; Petrucelli, Leonard; Sattler, Rita; Zarnescu, Daniela C.; Glass, Jonathan D.; Rossol, 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, RV, Zhang, Y, Petrucelli, L, Sattler, R, Zarnescu, DC, Glass, JD & Rossol, 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 V ; Zhang, Yongjie ; Petrucelli, Leonard ; Sattler, Rita ; Zarnescu, Daniela C. ; Glass, Jonathan D. ; Rossol, 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.
@article{cb1e9b08081548dda65a3cf40f43eb0d,
title = "TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD",
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.",
author = "Chou, {Ching Chieh} and Yi Zhang and Umoh, {Mfon E.} and Vaughan, {Spencer W.} and Ileana Lorenzini and Feilin Liu and Melissa Sayegh and Donlin-Asp, {Paul G.} and Chen, {Yu Han} and Duong, {Duc M.} and Seyfried, {Nicholas T.} and Powers, {Maureen A.} and Thomas Kukar and Hales, {Chadwick M.} and Marla Gearing and Cairns, {Nigel J.} and Boylan, {Kevin B.} and Dickson, {Dennis W} and Rademakers, {Rosa V} and Yongjie Zhang and Leonard Petrucelli and Rita Sattler and Zarnescu, {Daniela C.} and Glass, {Jonathan D.} and Wilfried Rossol",
year = "2018",
month = "2",
day = "1",
doi = "10.1038/s41593-017-0047-3",
language = "English (US)",
volume = "21",
pages = "228--239",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

AU - Chou, Ching Chieh

AU - Zhang, Yi

AU - Umoh, Mfon E.

AU - Vaughan, Spencer W.

AU - Lorenzini, Ileana

AU - Liu, Feilin

AU - Sayegh, Melissa

AU - Donlin-Asp, Paul G.

AU - Chen, Yu Han

AU - Duong, Duc M.

AU - Seyfried, Nicholas T.

AU - Powers, Maureen A.

AU - Kukar, Thomas

AU - Hales, Chadwick M.

AU - Gearing, Marla

AU - Cairns, Nigel J.

AU - Boylan, Kevin B.

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

AU - Zhang, Yongjie

AU - Petrucelli, Leonard

AU - Sattler, Rita

AU - Zarnescu, Daniela C.

AU - Glass, Jonathan D.

AU - Rossol, Wilfried

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85041663633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041663633&partnerID=8YFLogxK

U2 - 10.1038/s41593-017-0047-3

DO - 10.1038/s41593-017-0047-3

M3 - Article

VL - 21

SP - 228

EP - 239

JO - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

IS - 2

ER -