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.

• Authors: 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
• Journal: Nature neuroscience (Nat Neurosci) Vol. 21 Issue 2 Pg. 228-239 (02 2018) ISSN: 1546-1726 [Electronic] United States
• PMID: 29311743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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