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

Nat Neurosci 2018 02 8;21(2):228-239. Epub 2018 Jan 8.

Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-017-0047-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800968PMC
February 2018

Publication Analysis

Top Keywords

nuclear pore
12
nucleocytoplasmic transport
12
mutant tdp-43
4
mislocalization nucleoporins
4
and/or mislocalization
4
sequestration and/or
4
triggered sequestration
4
nucleoporins transport
4
tdp-43 triggered
4
transport factors
4
import rna
4
rna export
4
protein import
4
nuclear protein
4
factors interfered
4
interfered nuclear
4
disease-linked mutant
4
machinery aggregated
4
interactome detergent-insoluble
4
detergent-insoluble tdp-43
4

Similar Publications