Abstract
Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive and lethal degenerative disorder that affects motoneurons in the brain and spinal cord
Analysis of tissues lysates obtained from TDP-43A315T transgenic animals at end-stage indicated similar overexpression levels of Tar DNA binding protein 43 (TDP-43) in both frontal cortex and spinal cord of male and female animals (Fig. 1C)
The levels of glial activation observed in mutant TDP-43 mice were comparable to the signal observed in symptomatic SOD1G93A mice. These results indicate that TDP-43A315T transgenic mice develop neurodegeneration and glial activation in the spinal cord, resembling the histopathological changes observed in classical amyotrophic lateral sclerosis (ALS) models
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive and lethal degenerative disorder that affects motoneurons in the brain and spinal cord. Several animal models to study TDP-43 pathogenesis have been developed in mouse and rats with a variety of phenotypes and histopathological features (reviewed in ref.[16]). Transgenic mice expressing TDP-43WT in the hippocampus, cortex and striatum develop learning and memory deficits, as well as altered motor control 20. Gliosis is detected in most mouse models overexpressing TDP-43WT 17,19–21 In these models, ubiquitin positive cytoplasmic inclusions can be found in spinal cord motoneurons and brainstem neurons. Motor and cognitive alterations have been found in mice expressing TDP43A315T mutant at 3 months of age[23] All these studies suggest that different patterns of TDP-43 expression result in either motor dysfunctions or behavioral alterations depending on the tissue and levels of transgene expression, generating a phenotype resembling FTD-ALS. None of the models described so far are optimal to study ALS because of the apparent absence of motoneurons degeneration
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
