SHARED GLIAL DYSFUNCTION ACROSS THREE CEREBELLAR ATAXIAS REVEALS CONVERGENT MECHANISMS OF PURKINJE CELLS VULNERABILITY

Cerebellar ataxias represent a diverse group of rare genetic neurodegenerative diseases characterized by cerebellar dysfunction and prominent Purkinje cell (PC) degeneration, resulting in loss of coordination and ataxia symptoms. Yet, the mechanisms underlying the selective vulnerability of PCs remain incompletely understood and may involve non-cell autonomous process. To identify convergent pathogenic pathways, we performed single-cell transcriptomic analyses of three mouse models of cerebellar ataxia, Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 7 (SCA7), and Friedreich’s ataxia (FA), at two stages of disease progression. This approach revealed shared dysregulated pathways across multiple cerebellar cell populations. Among the most promising altered pathways, genes encoding Bergmann glia-secreted matricellular proteins were found to be significantly dysregulated in the three models. In line with these in silico data, we observed structural alterations of Bergmann glia radial processes, and a reduction in the levels of several Bergmann glia-secreted synapse-modulating proteins in the cerebellum of each model. Given the essential role of astroglia in synapse formation, maintenance, elimination and function, we will now dissect and experimentally modulate this dysregulated pathway to determine its contribution to the loss of the glutamatergic synaptic contacts onto PCs. Together our data suggest an early Bergmann glia pathology that likely contributes to the characteristic PC degeneration observed in most cerebellar ataxias.