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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.

DOI: doi:10.1242/dmm.047548

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
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