|ZFIN ID: ZDB-PUB-180627-10|
Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons
Svahn, A.J., Don, E.K., Badrock, A.P., Cole, N.J., Graeber, M.B., Yerbury, J.J., Chung, R., Morsch, M.
|Source:||Acta Neuropathologica 136(3): 445-459 (Journal)|
|Registered Authors:||Badrock, Andrew P., Chung, Roger, Cole, Nicholas, Don, Emily, Morsch, Marco, Svahn, Adam|
|Keywords:||Amyotrophic lateral sclerosis (ALS), Microglia, Motor neuron disease (MND), Neurodegeneration, Pathological spreading, TDP-43, Zebrafish|
|PubMed:||29943193 Full text @ Acta Neuropathol.|
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.
ABSTRACTTransactivating 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.