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

Nat Neurosci. 2018 Feb;21(2):228-239. doi: 10.1038/s41593-017-0047-3. Epub 2018 Jan 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Active Transport, Cell Nucleus / physiology*
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • Animals, Genetically Modified
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism
  • C9orf72 Protein / ultrastructure
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / ultrastructure
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Embryo, Nonmammalian
  • Female
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / metabolism
  • Frontotemporal Dementia* / pathology
  • Humans
  • Larva
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroblastoma / pathology
  • Nuclear Envelope / pathology
  • Nuclear Envelope / ultrastructure
  • Nuclear Pore / genetics
  • Nuclear Pore / metabolism*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology

Substances

  • C9orf72 Protein
  • DNA-Binding Proteins
  • Drosophila Proteins
  • TDP-43 protein, human