Nucleo-cytoplasmic transport of TDP-43 studied in real time

impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

Adam J. Svahn, Emily K. Don, Andrew P. Badrock, Nicholas J. Cole, Manuel B. Graeber, Justin J. Yerbury, Roger Chung*, Marco Morsch

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)
31 Downloads (Pure)

Abstract

Transactivating DNA-binding protein-43 (TDP-43) deposits represent a typical finding in almost all ALS patients, more than half of FTLD patients and patients with several other neurodegenerative disorders. It appears that perturbation of nucleo-cytoplasmic transport is an important event in these conditions but the mechanistic role and the fate of TDP-43 during neuronal degeneration remain elusive. We have developed an experimental system for visualising the perturbed nucleocytoplasmic transport of neuronal TDP-43 at the single-cell level in vivo using zebrafish spinal cord. This approach enabled us to image TDP-43-expressing motor neurons before and after experimental initiation of cell death. We report the formation of mobile TDP-43 deposits within degenerating motor neurons, which are normally phagocytosed by microglia. However, when microglial cells were depleted, injury-induced motor neuron degeneration follows a characteristic process that includes TDP-43 redistribution into the cytoplasm, axon and extracellular space. This is the first demonstration of perturbed TDP-43 nucleocytoplasmic transport in vivo, and suggests that impairment in microglial phagocytosis of dying neurons may contribute towards the formation of pathological TDP-43 presentations in ALS and FTLD.

Original languageEnglish
Pages (from-to)445-459
Number of pages15
JournalActa Neuropathologica
Volume136
Issue number3
Early online date25 Jun 2018
DOIs
Publication statusPublished - Sep 2018

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Microglia
  • Motor neuron disease (MND)
  • Neurodegeneration
  • Pathological spreading
  • TDP-43
  • Zebrafish

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