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

Autor: Svahn AJ; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia., Don EK; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia., Badrock AP; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia.; Faculty of Life Sciences, The University of Manchester, Manchester, UK., Cole NJ; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia., Graeber MB; Brain Tumor Research Laboratories, Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia., Yerbury JJ; Faculty of Science, Medicine and Health, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia., Chung R; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia. roger.chung@mq.edu.au., Morsch M; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia. marco.morsch@mq.edu.au.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2018 Sep; Vol. 136 (3), pp. 445-459. Date of Electronic Publication: 2018 Jun 25.
DOI: 10.1007/s00401-018-1875-2
Abstrakt: 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.
Databáze: MEDLINE
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