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 Zhang; Leonard Petrucelli; Rita Sattler; Daniela C Zarnescu; Jonathan D Glass; Wilfried Rossoll

doi:10.1038/s41593-017-0047-3

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

Nat Neurosci. 2018 Feb;21(2):228-239. doi: 10.1038/s41593-017-0047-3. Epub 2018 Jan 8.

Authors

Ching-Chieh Chou^{1

2

3}, Yi Zhang^{1

4

5}, Mfon E Umoh^{2

6}, Spencer W Vaughan⁷, Ileana Lorenzini⁸, Feilin Liu^{9

10}, Melissa Sayegh⁷, Paul G Donlin-Asp^{1

11}, Yu Han Chen¹, Duc M Duong^{2

12}, Nicholas T Seyfried^{2

6

12}, Maureen A Powers¹, Thomas Kukar^{2

6

13}, Chadwick M Hales^{2

6}, Marla Gearing^{2

6

14}, Nigel J Cairns¹⁵, Kevin B Boylan¹⁶, Dennis W Dickson⁹, Rosa Rademakers⁹, Yong-Jie Zhang⁹, Leonard Petrucelli⁹, Rita Sattler⁸, Daniela C Zarnescu⁷, Jonathan D Glass^{2

6

17}, Wilfried Rossoll^{18

19

20}

Affiliations

¹ Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.
² Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
³ Department of Biology, Stanford University, Stanford, CA, USA.
⁴ Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
⁵ Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, USA.
⁸ Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.
⁹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China.
¹¹ Max Planck Institute for Brain Research, Frankfurt, Germany.
¹² Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹⁵ Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.
¹⁶ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹⁷ Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA.
¹⁸ Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA. rossoll.wilfried@mayo.edu.
¹⁹ Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA. rossoll.wilfried@mayo.edu.
²⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. rossoll.wilfried@mayo.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / genetics
Active Transport, Cell Nucleus / physiology*
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
Animals, Genetically Modified
C9orf72 Protein / genetics
C9orf72 Protein / metabolism
C9orf72 Protein / ultrastructure
Cells, Cultured
Cerebral Cortex / cytology*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
DNA-Binding Proteins / ultrastructure
Drosophila
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Embryo, Nonmammalian
Female
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / metabolism
Frontotemporal Dementia* / pathology
Humans
Larva
Male
Mice
Mice, Inbred C57BL
Neuroblastoma / pathology
Nuclear Envelope / pathology
Nuclear Envelope / ultrastructure
Nuclear Pore / genetics
Nuclear Pore / metabolism*
Protein Aggregation, Pathological / metabolism
Protein Aggregation, Pathological / pathology

Substances

C9orf72 Protein
DNA-Binding Proteins
Drosophila Proteins
TARDBP protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding