How does mutant ATXN1 expression in microglia impact Spinocerebellar Ataxia Type 1 pathogenesis? - Project Summary How does mutant ATXN1 expression in microglia impact Spinocerebellar Ataxia Type 1 pathogenesis? Spinocerebellar ataxia type 1 (SCA1) is a fatal autosomal dominant neurodegenerative disease without a cure or effective therapies to delay disease onset and progression. SCA1 is caused by a CAG repeat expansion that encodes for a polyglutamine stretch in the ATAXIN-1(ATXN1) protein and is characterized by deficits in motor coordination, dysarthria, and premature death. Prior work has uncovered increased numbers of microglia, microglia contribution to SCA1 motor phenotypes, and differentially expressed genes in SCA1 microglia. However, there is still a critical need to understand whether these phenotypes are due to mutant ATXN1 (mATXN1) expression in microglia or surrounding cells. The goal of my proposal is to determine the role microglial mATXN1 expression plays in motor behavior, microglia molecular phenotypes, and the impact on surrounding cells. I aim to achieve this by removing mATXN1 from microglia by crossing Lyve1CRE mice with f- ATXN1146Q/2Q mice. The f-ATXN1146Q/2Q mouse model contains LoxN sites around mATXN1 allowing for conditional deletion of mATXN1 with Cre recombinase expression. The Lyve1CRE model highly expresses Cre recombinase in microglia and macrophages. Crossing these two mice will generate f-ATXN1146Q/2Q;Lyve1CRE mice which will have mATXN1 deleted from microglia and macrophages. I aim to assess the impact of removing mATXN1 expression in microglia on motor deficits, microglia disease phenotypes, and cerebellar pathogenesis. Motor function will be assessed through battery of motor assay. Microglia disease phenotypes and cerebellar pathogenesis will be assessed with a combination of single nuclei and bulk RNA sequencing and immunohistochemistry. I hypothesize that removal of mATXN1 will ameliorate motor deficits, correct the number of differentially expressed genes in microglia and other cerebellar cells, and ameliorate microglial reactivity and cerebellar pathology seen through immunohistochemistry. This research will aid in further elucidating the role microglia plays in SCA1, a relatively understudied aspect of SCA1. Finally, the training I will receive during this work is paramount to my goal to become faculty at research university.
