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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  VPS 4B upon  TDP ‐43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that  TDP ‐43 represses  VPS 4B 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.

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