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

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Dyer, MS, Woodhouse, A ORCID: 0000-0002-4246-7624 and Blizzard, CA ORCID: 0000-0002-8683-2937 2021 , 'Cytoplasmic human TDP-43 mislocalization induces widespread dendritic spine loss in mouse upper motor neurons' , Brain Sciences, vol. 11, no. 7 , pp. 1-16 , doi: 10.3390/brainsci11070883.

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Abstract

Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lowermotor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containingthe DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalizationof TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliestdetectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigatedhow mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracyclineinducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannotenter the nucleus (TDP-43∆NLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH miceto visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WTand controls, TDP-43∆NLS drove a robust loss in spine density in all the dendrite regions of theupper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in thegeneration of network dysfunction in ALS likely through impacting the formation or durability ofexcitatory synapses. These findings are relevant to the vast majority of ALS cases, and providesfurther evidence that upper motor neurons may need to be protected from TDP-43 mediated synapticexcitatory changes early in disease.

Item Type: Article
Authors/Creators:Dyer, MS and Woodhouse, A and Blizzard, CA
Keywords: amyotrophic lateral sclerosis, TDP-43, dendrite spine
Journal or Publication Title: Brain Sciences
Publisher: MDPI AG
ISSN: 2076-3425
DOI / ID Number: 10.3390/brainsci11070883
Copyright Information:

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/).

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