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bioRxiv · 10.1101/2025.10.01.679786

TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD

Vassallu, F.·Lopez, M.·Lopez Ambrosioni, F.·Casal, J.·Caltana, L.·Igaz, L. M.
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Abstract

TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-{Delta}NLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analysed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both transgenic TDP-43-{Delta}NLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-{Delta}NLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model. HighlightsO_LICytoplasmic TDP-43 expression in vivo causes early synaptic and mitochondrial abnormalities. C_LIO_LIReduced synaptic density observed in cortical and hippocampal regions of TDP-43-{Delta}NLS mice. C_LIO_LISynaptic ultrastructure altered, including increased cleft width and reduced PSD thickness. C_LIO_LIRegion-specific mitochondrial density changes: increased in cortex, decreased in hippocampus. C_LIO_LIFindings link TDP-43 mislocalization to early structural and functional brain deficits. C_LI

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Vassallu, F., Lopez, M., Lopez Ambrosioni, F., Casal, J., Caltana, L., Igaz, L. M.. 2025-10-02. TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD. https://doi.org/10.1101/2025.10.01.679786

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