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Cytoplasmic human TDP-43 mislocalization induces widespread dendritic spine loss in mouse upper motor neurons

Citation

Dyer, MS and Woodhouse, A and Blizzard, CA, Cytoplasmic human TDP-43 mislocalization induces widespread dendritic spine loss in mouse upper motor neurons, Brain Sciences, 11, (7) pp. 1-16. ISSN 2076-3425 (2021) [Refereed Article]


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Copyright Statement

Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).

DOI: doi:10.3390/brainsci11070883

Abstract

Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliest detectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigated how mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracycline inducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannot enter the nucleus (TDP-43∆NLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH mice to visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WT and controls, TDP-43∆NLS drove a robust loss in spine density in all the dendrite regions of the upper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in the generation of network dysfunction in ALS likely through impacting the formation or durability of excitatory synapses. These findings are relevant to the vast majority of ALS cases, and provides further evidence that upper motor neurons may need to be protected from TDP-43 mediated synaptic excitatory changes early in disease.

Item Details

Item Type:Refereed Article
Keywords:amyotrophic lateral sclerosis, TDP-43, dendrite spine
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Dyer, MS (Mr Marcus Dyer)
UTAS Author:Woodhouse, A (Dr Adele Woodhouse)
UTAS Author:Blizzard, CA (Dr Catherine Blizzard)
ID Code:147036
Year Published:2021
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-10-11
Last Modified:2021-11-04
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