TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons

EMBO J. 2016 Nov 2;35(21):2350-2370. doi: 10.15252/embj.201694221. Epub 2016 Sep 12.


Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.

Keywords: ALS; ErbB4; FTLD; TDP‐43; recycling endosomes.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endosomal Sorting Complexes Required for Transport / genetics*
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Endosomes / metabolism*
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / metabolism
  • Gene Knockdown Techniques
  • Hippocampus / cytology
  • Humans
  • Neurons / metabolism*
  • Protein Transport
  • Rats
  • Receptor, ErbB-4 / genetics
  • Receptor, ErbB-4 / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Signal Transduction


  • CHMP2B protein, human
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • TARDBP protein, human
  • ERBB4 protein, human
  • FGFR1 protein, human
  • Receptor, ErbB-4
  • Receptor, Fibroblast Growth Factor, Type 1
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities
  • VPS4B protein, human