TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

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 ZhangLeonard Petrucelli, Rita Sattler, Daniela C. Zarnescu, Jonathan D. Glass, Wilfried Rossoll

Research output: Contribution to journalArticlepeer-review

163 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalNature Neuroscience
Issue number2
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • General Neuroscience


Dive into the research topics of 'TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD'. Together they form a unique fingerprint.

Cite this