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

Abstract

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. Pathological TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 pathology alters the morphology of nuclear pore complexes and cause deficits in nucleocytoplasmic transport.

Cited by papers we hold 18

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• Mass spectrometry‐based protein–protein interaction networks for the study of human diseases · 2021
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• Nucleo–cytoplasmic transport defects and protein aggregates in neurodegeneration · 2020
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• Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress · 2020
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• The role of TDP-43 mislocalization in amyotrophic lateral sclerosis · 2020
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• Disrupted neuronal trafficking in amyotrophic lateral sclerosis · 2019
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• The mutational landscape of a prion-like domain · 2019
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• Motor Neuron Susceptibility in ALS/FTD · 2019
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• Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia · 2019
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• The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD · 2019
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• Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1 · 2018
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• Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo · 2018
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• Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases · 2018
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