Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases

脊髓小脑性共济失调1型（SCA1）是一种常染色体显性的进行性神经退行性疾病

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, progressive neurodegenerative disease that causes severe motor deficits and cerebellar neuron degeneration. It is caused by a CAG-repeat expansion in the gene Ataxin-1 (ATXN1). Although ATXN1 is fairly ubiquitously expressed throughout the brain, specific brain regions and cell types have been shown to be selectively vulnerable to degeneration, including cerebellar Purkinje cell neurons. In order to better understand the pathophysiology of this disease, several mouse models have been developed and extensively utilized. However, most of these mouse models have been characterized on a particular genetic background. For example, the Purkinje cell-specific transgenic SCA1 models have been developed and maintained on a pure FVB/NJ background, including the B05 model, which express the human disease-causing ATXN1 allele and recapitulate the behavioral deficits and pathological phenotypes observed in human SCA1 patients. Interestingly, when we backcrossed and maintained this original B05 mouse line onto a pure C57BL/6J genetic background, the SCA1-related behavioral motor deficit was no longer observed, however the Purkinje cell degeneration phenotypes remained. These preliminary findings suggest that mouse genetic background plays a crucial role in effectively modeling neurodegenerative diseases, such as SCA1, and therefore, the interaction of mouse genetic background and disease symptoms should be further analyzed and carefully controlled for in future experiments. In this supplement grant proposal, we will determine the precise impact of different mouse genetic backgrounds towards SCA1 disease phenotypes, and elucidate the molecular mechanisms through which mutant ATXN1 regulates motor behavior deficits and Purkinje cell degeneration. In Aim 1, we will fully characterize the SCA1 mouse phenotypic differences between the two genetic backgrounds. In Aim 2, we will determine the molecular pathways differentially affected in the SCA1 mouse cerebellum between two different genetic backgrounds. We anticipate that this research will provide fundamental insights into the impact of mouse genetic backgrounds towards neurodegenerative disease pathogenesis, and uncover novel mechanisms through which SCA1 pathology is regulated. If successful, these studies will underscore the importance of examining multiple genetic backgrounds in neurodegenerative diseases and reveal novel potential entry points for therapeutic intervention in disorders in which ATXN1 mutations are associated, including SCA1, frontotemporal dementia, and Alzheimer’s disease.