Biology subjects

Igaz, L. M.

Publications and source records attributed to Igaz, L. M..

3 recordsLinked to original sources

bioRxiv2026

Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies

Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-{Delta}NLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following one month of transgene expression. Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC and hippocampal subfields. hTDP-43-{Delta}NLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-{Delta}NLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, supports the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies. These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.

neuroscience↗

bioRxiv2025

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

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

neuroscience↗

bioRxiv2025

Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model

TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal ({Delta}NLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans, they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors--including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter--with the cytoplasmic {Delta}NLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.

neuroscience↗