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TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy
Citation
Atkinson, RAK and Leung, J and Bender, J and Kirkcaldie, M and Vickers, J and King, A, TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy, Disease Models & Mechanisms, 14, (2) pp. 1-14. ISSN 1754-8403 (2021) [Refereed Article]
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Copyright Statement
© 2021. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License (https://creativecomons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Abstract
Mislocalization of the TAR DNA-binding protein 43 (TDP-43; encoded
by TARDBP) from the nucleus to the cytoplasm is a common feature of
neurodegenerative conditions such as amyotrophic lateral sclerosis
(ALS) and frontotemporal lobar degeneration (FTLD). The downstream
in vivo cellular effects of this mislocalization are not well understood. To
investigate the impact of mislocalized TDP-43 on neuronal cell bodies,
axons and axonal terminals, we utilized the mouse visual system to
create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal
ganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation in
the nuclear localization sequence (hTDP-ΔNLS-GFP), to cause TDP-43
mislocalization, with∼60% transduction efficiency achieved. Expression
of both hTDP-WT-GFP and hTDP-ΔNLS-GFP resulted in changes to
neurofilament expression, with cytoplasmic TDP-43 being associated
with significantly (P<0.05) increased neurofilament heavy expression in
the cell soma, and both forms of altered TDP-43 leading to significantly
(P<0.05) decreased numbers of neurofilament-positive axons within the
optic nerve. Alterations to neurofilament proteins were associated with
significantly (P<0.05) increased microglial density in the optic nerve and
retina. Furthermore, expression of hTDP-WT-GFP was associated with
a significant (P<0.05) increase in pre-synaptic input into RGCs in the
retina. The current study has developed a new model that allows
detailed examination of alterations to TDP-43 and will contribute to the
knowledge of TDP-43-mediated neuronal alterations and degeneration.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, neurodegeneration, disease model, visual system |
| Research Division: | Biomedical and Clinical Sciences |
| Research Group: | Neurosciences |
| Research Field: | Neurology and neuromuscular diseases |
| Objective Division: | Expanding Knowledge |
| Objective Group: | Expanding knowledge |
| Objective Field: | Expanding knowledge in the health sciences |
| UTAS Author: | Atkinson, RAK (Dr Rachel Atkinson) |
| UTAS Author: | Leung, J (Dr Jacqueline Leung) |
| UTAS Author: | Bender, J (Mr James Bender) |
| UTAS Author: | Kirkcaldie, M (Dr Matthew Kirkcaldie) |
| UTAS Author: | Vickers, J (Professor James Vickers) |
| UTAS Author: | King, A (Professor Anna King) |
| ID Code: | 145457 |
| Year Published: | 2021 |
| Web of Science® Times Cited: | 1 |
| Deposited By: | Wicking Dementia Research and Education Centre |
| Deposited On: | 2021-07-22 |
| Last Modified: | 2021-09-02 |
| Downloads: | 2 View Download Statistics |
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