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[O2–18–01]: TDP‐43 PATHOLOGY DISRUPTS NUCLEAR PORE COMPLEXES AND NUCLEOCYTOPLASMIC TRANSPORT IN ALS/FTD
Author(s) -
Chou ChingChieh,
Zhang Yi,
Umoh Mfon,
Seyfried Nicholas T.,
Powers Maureen,
Kukar Thomas,
Boylan Kevin,
Dickson Dennis W.,
Rademakers Rosa,
Zarnescu Daniela,
Glass Jonathan,
Rossoll Wilfried
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.247
Subject(s) - nuclear pore , nuclear transport , microbiology and biotechnology , cytoplasm , protein aggregation , stress granule , nuclear protein , frontotemporal dementia , nucleoporin , ubiquitin , amyotrophic lateral sclerosis , rna , neurodegeneration , interactome , biology , cell nucleus , chemistry , pathology , biochemistry , medicine , dementia , messenger rna , disease , translation (biology) , gene , transcription factor
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.