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Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

Journal Article


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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.

Authors


  •   Svahn, Adam (external author)
  •   Don, Emily (external author)
  •   Badrock, Andrew (external author)
  •   Cole, Nicholas (external author)
  •   Graeber, Manuel B. (external author)
  •   Yerbury, Justin J.
  •   Chung, Roger (external author)
  •   Morsch, Marco (external author)

Publication Date


  • 2018

Citation


  • Svahn, A. J., Don, E. K., Badrock, A. P., Cole, N. J., Graeber, M. B., Yerbury, J. J., Chung, R. & Morsch, M. (2018). Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons. Acta Neuropathologica, 136 (3), 445-459.

Scopus Eid


  • 2-s2.0-85049055050

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1098&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/97

Number Of Pages


  • 14

Start Page


  • 445

End Page


  • 459

Volume


  • 136

Issue


  • 3

Place Of Publication


  • Germany

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.

Authors


  •   Svahn, Adam (external author)
  •   Don, Emily (external author)
  •   Badrock, Andrew (external author)
  •   Cole, Nicholas (external author)
  •   Graeber, Manuel B. (external author)
  •   Yerbury, Justin J.
  •   Chung, Roger (external author)
  •   Morsch, Marco (external author)

Publication Date


  • 2018

Citation


  • Svahn, A. J., Don, E. K., Badrock, A. P., Cole, N. J., Graeber, M. B., Yerbury, J. J., Chung, R. & Morsch, M. (2018). Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons. Acta Neuropathologica, 136 (3), 445-459.

Scopus Eid


  • 2-s2.0-85049055050

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1098&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/97

Number Of Pages


  • 14

Start Page


  • 445

End Page


  • 459

Volume


  • 136

Issue


  • 3

Place Of Publication


  • Germany