by
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 Seyfried;
Maureen Powers;
Thomas Kukar;
Chad 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 O Rossoll
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.