TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy
journal contributionposted on 2023-05-21, 00:59 authored by Rachel AtkinsonRachel Atkinson, Jacqueline LeungJacqueline Leung, James BenderJames Bender, Matthew KirkcaldieMatthew Kirkcaldie, James VickersJames Vickers, Anna KingAnna King
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 titleDisease Models & Mechanisms
Department/SchoolWicking Dementia Research Education Centre
PublisherCompany of Biologists Ltd.
Place of publicationUnited Kingdom
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