TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
| Autor: | Daniela C. Zarnescu, Spencer Vaughan, Maureen A. Powers, Feilin Liu, Ching Chieh Chou, Chadwick M. Hales, Kevin B. Boylan, Yi Zhang, Marla Gearing, Thomas Kukar, Nicholas T. Seyfried, Melissa Sayegh, Wilfried Rossoll, Duc M. Duong, Mfon E. Umoh, Leonard Petrucelli, Paul G. Donlin-Asp, Rita Sattler, Yu Han Chen, Dennis W. Dickson, Jonathan D. Glass, Yong Jie Zhang, Ileana Lorenzini, Rosa Rademakers, Nigel J. Cairns |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Embryo Nonmammalian Nuclear Envelope Active Transport Cell Nucleus Protein aggregation Protein Aggregation Pathological TARDBP Article Animals Genetically Modified Mice Neuroblastoma 03 medical and health sciences 0302 clinical medicine C9orf72 mental disorders medicine Animals Drosophila Proteins Humans Nuclear pore Nuclear protein Cells Cultured Cerebral Cortex C9orf72 Protein Chemistry General Neuroscience Amyotrophic Lateral Sclerosis nutritional and metabolic diseases 3. Good health nervous system diseases Mice Inbred C57BL DNA-Binding Proteins 030104 developmental biology Nucleocytoplasmic Transport Frontotemporal Dementia Larva Nuclear Pore Drosophila Female Nucleoporin Human medicine 030217 neurology & neurosurgery |
| Zdroj: | Nature neuroscience |
| ISSN: | 1546-1726 1097-6256 |
| Popis: | 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 (NPC) and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins (Nups) and transport factors (TFs), and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts, and iPSC-derived neurons. Nuclear pore pathology is present in brain tissue from sporadic ALS cases (sALS) and those with genetic mutations in TARDBP (TDP-ALS) and C9orf72 (C9-ALS). Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD. |
| Databáze: | OpenAIRE |
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