Vijayakumar, B. G. | bioRxiv Science

bioRxiv2024

A robust evaluation of TDP-43, poly GP, cellular pathology, and behavior in a AAV-C9ORF72 (G4C2)66 mouse model

The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.

neuroscience↗

bioRxiv2022

Astrocyte MCT1 expression does not contribute to the axonal degenerative phenotype observed with ubiquitous MCT1 depletion.

We recently reported that loss of oligodendrocyte metabolic support through the lactate and pyruvate transporter Monocarboxylate Transporter 1 (MCT1) is well tolerated into adulthood. Only with advanced aging did we observe axonal degeneration and hypomyelination due to loss of MCT1 from oligodendroglia lineage cells. MCT1 is also expressed by other glial subtypes, such as astrocytes and endothelial cells where it has been suggested to be essential for learning and memory tasks. However, the importance of MCT1 in these cell types for long-term axonal metabolic support is still unknown. We therefore addressed whether conditional loss of MCT1 from either of these cell types would lead to widespread axonal degeneration with aging. Using a conditional null approach, similar to what was used for oligodendrocyte MCT1 depletion, we observed that conditional knockout of MCT1 from either astrocytes or endothelial cells did not cause neuronal injury. On the other hand, inducible ubiquitous depletion of MCT1 causes late-onset axonal degeneration, comparable with what was observed in our previous study using the oligodendrocyte lineage MCT1 null mice. In summary, we conclude that unlike oligodendrocyte MCT1, astrocyte MCT1 is not an essential driver of astrocyte mediated axonal energy homeostasis with aging.

neuroscience↗