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

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

Author information

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.

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PMID:
29311743
PMCID:
PMC5800968
DOI:
10.1038/s41593-017-0047-3
[Indexed for MEDLINE]
Free PMC Article

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