PUBLICATION
Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons
- Authors
- Svahn, A.J., Don, E.K., Badrock, A.P., Cole, N.J., Graeber, M.B., Yerbury, J.J., Chung, R., Morsch, M.
- ID
- ZDB-PUB-180627-10
- Date
- 2018
- 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
- MeSH Terms
-
- Animals
- Axons/metabolism*
- Axons/pathology
- DNA-Binding Proteins/metabolism*
- Microglia/metabolism*
- Microglia/pathology
- Motor Neurons/metabolism*
- Motor Neurons/pathology
- Nerve Degeneration/metabolism*
- Nerve Degeneration/pathology
- Protein Transport
- Zebrafish
- Zebrafish Proteins/metabolism*
- PubMed
- 29943193 Full text @ Acta Neuropathol.
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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping