Tdp-43 Pathology Disrupts Nuclear Pore Complexes And Nucleocytoplasmic Transport In Als/Ftd
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.
Digital Object Identifier (DOI)
Chou, Ching Chieh; Zhang, Yi; Umoh, Mfon E.; Vaughan, Spencer W.; Lorenzini, Ileana; Liu, Feilin; Sayegh, Melissa; Donlin-Asp, Paul G.; Chen, Yu Han; Duong, Duc M.; Seyfried, Nicholas T.; Powers, Maureen A.; Kukar, Thomas; Hales, Chadwick M.; Gearing, Marla; Cairns, Nigel J.; Boylan, Kevin B.; Dickson, Dennis W.; Rademakers, Rosa; Zhang, Yong Jie; Petrucelli, Leonard; Sattler, Rita; Zarnescu, Daniela C.; Glass, Jonathan D.; and Rossoll, Wilfried, "Tdp-43 Pathology Disrupts Nuclear Pore Complexes And Nucleocytoplasmic Transport In Als/Ftd" (2018). Translational Neuroscience. 372.