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

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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.


Publication title

Disease Models & Mechanisms








Wicking Dementia Research Education Centre


Company of Biologists Ltd.

Place of publication

United Kingdom

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© 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 (, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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  • Open

Socio-economic Objectives

Treatment of human diseases and conditions; Expanding knowledge in the health sciences