Nuclear pore

Pathology

Neuroscience

C9orf72

Disease

Dementia

Nuclear protein

Nuclear transport

Nucleoporin

Transcription factor

Biology

Gene

Induced pluripotent stem cell

Protein aggregation

Mutant

Embryonic stem cell

Cytoplasm

SOD1

Neurodegeneration

Frontotemporal dementia

Cell nucleus

Amyotrophic lateral sclerosis

TARDBP

Cell biology

Interactome

Genetics

Medicine

Nature Neuroscience

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.

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