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TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy

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Atkinson, RAK ORCID: 0000-0002-9846-7738, Leung, J ORCID: 0000-0001-8798-3932, Bender, J, Kirkcaldie, M ORCID: 0000-0003-3285-0168, Vickers, J ORCID: 0000-0001-5671-4879 and King, A ORCID: 0000-0003-1792-0965 2021 , 'TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy' , Disease Models & Mechanisms, vol. 14, no. 2 , pp. 1-14 , doi: 10.1242/dmm.047548.

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Abstract

Mislocalization of the TAR DNA-binding protein 43 (TDP-43; encodedby TARDBP) from the nucleus to the cytoplasm is a common feature ofneurodegenerative conditions such as amyotrophic lateral sclerosis(ALS) and frontotemporal lobar degeneration (FTLD). The downstreamin vivo cellular effects of this mislocalization are not well understood. Toinvestigate the impact of mislocalized TDP-43 on neuronal cell bodies,axons and axonal terminals, we utilized the mouse visual system tocreate a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinalganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation inthe nuclear localization sequence (hTDP-ΔNLS-GFP), to cause TDP-43mislocalization, with∼60% transduction efficiency achieved. Expressionof both hTDP-WT-GFP and hTDP-ΔNLS-GFP resulted in changes toneurofilament expression, with cytoplasmic TDP-43 being associatedwith significantly (PPPP<0.05) increase in pre-synaptic input into RGCs in theretina. The current study has developed a new model that allowsdetailed examination of alterations to TDP-43 and will contribute to theknowledge of TDP-43-mediated neuronal alterations and degeneration.

Item Type: Article
Authors/Creators:Atkinson, RAK and Leung, J and Bender, J and Kirkcaldie, M and Vickers, J and King, A
Keywords: TDP-43, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, neurodegeneration, disease model, visual system
Journal or Publication Title: Disease Models & Mechanisms
Publisher: Company of Biologists Ltd.
ISSN: 1754-8403
DOI / ID Number: 10.1242/dmm.047548
Copyright Information:

© 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.

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