Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia

Abstract Friedreich’s ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, some of the main symptoms observed in affected individuals. Similar to other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in Friedreich’s ataxia. In this work, we have followed and characterized the progression of changes in the cerebellar cortex of the latest Friedreich’s ataxia humanized mouse model, the YG8-800 (Fxn null :YG8s(GAA)>800), which carries a human FXN transgene containing more than 800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between Y47R control and YG8-800 mice at different time points. Our findings revealed that the YG8-800 mice display an ataxic phenotype, characterized by poor motor coordination, lower body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration along with an increased expression of key pro-inflammatory cytokines and downregulation of neurotrophic factors. Together, our results show how the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in the human condition. Accordingly, this humanized model could represent a valuable tool to study Friedreich’s ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.