Disorders of the Nervous System
Author: Pablo Silva Pintos | email: pablosilvapinto@gmail.com
Pablo Silva 1°, Jorge Goldstein 2°, Laura Caltana 3°, Lionel Muller Igaz 1°
1° IFIBIO Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires – CONICET, Buenos Aires, Argentina
2° IFIBIO Houssay, Laboratorio de Neurofisiopatología, Facultad de Medicina, Universidad de Buenos Aires – CONICET, Buenos Aires, Argentina
3° IBCN (CONICET), University of Buenos Aires School of Medicine, Buenos Aires, Argentina
TDP-43 proteinopathy is the main pathology in amyotrophic lateral sclerosis and frontotemporal dementia, suggesting that these diseases share underlying mechanisms. We generated transgenic mice conditionally overexpressing human wild-type TDP-43 protein in forebrain neurons, recapitulating core features of FTD/ALS. However, the role of TDP-43 in neurodegeneration is still unclear. Here, we analyzed neuronal loss (using immunofluorescence against NeuN) in specific brain regions, including somatosensory (SSC) and motor (MC) cortices and hippocampal subfields. Our results show that after post-weaning transgene (TG) induction during 1 month, these mice display neurodegeneration on both SSC and MC, but not on hippocampal CA1 region. Moreover, after two weeks of TG suppression this phenotype is still present, indicates that the suppression protocol does not prevent early neuronal loss in this model. Ultrastructural analysis of suppressed animals by Transmission Electron Microscopy showed signs of perivascular and intracellular edema, accompanied by increased lumen of the rough endoplasmic reticulum in neurons, astrocytes and oligodendrocytes. Additionally, mitochondrial alterations with cristae disorganization, irregular formations composed of intracellular membranes and pyknotic nuclei were observed. Together, our findings contribute to understand disease mechanisms and specifically how TDP-43 dysregulation is associated with neurodegeneration and ultrastructural alterations.