Microglial Mutant ATXN1 Contribution to Disease phenotypes in Spinocerebellar Ataxia Type 1 Mice

Abstract

Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific roles of microglia intrinsic factors in microglial activation and disease pathogenesis remain unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by early microglial activation in models with Purkinje cell specific and ubiquitous expression of mutant ATXN1 (mATXN1). SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1(ATXN1) gene. Prior work has demonstrated that mATXN1 is involved in transcription, and preventing nuclear localization corrects SCA1 transcriptional alterations and disease phenotypes. Furthermore, previous studies have uncovered large numbers of DEGs in microglia with ubiquitous expression of mATXN1. What remains to be understood is how microglial mATXN1 expression contributes to disease phenotypes. To address this gap in knowledge, I used a genetic approach to delete mutant ATXN1 selectively in microglia in SCA1 mice (ATXN1ₘₖₒ). I hypothesized that ATXN1ₘₖₒ mice would exhibit ameliorated SCA1 microglial phenotype, surrounding cerebellar cell health, and SCA1-like behavioral phenotypes. I first sought to investigate microglia phenotype by reducing microglial mATXN1. I found that microglial mATXN1 reduction led to marked correction in transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching. Cerebellar pathology of Purkinje cells and astrocytes was also ameliorated. Utilizing a battery of behavioral tests, I found that microglial mutant ATXN1 reduction ameliorated cognitive, mood and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1 and contributes to SCA1 pathology and behavioral deficits.