Elucidating the contribution of lipid dysregulation to impaired oligodendrocyte maturation and myelination in Spinocerebellar ataxia type 3

ABSTRACT Oligodendrocytes (OLs) are a type of glial cells in the brain involved in the pathogenesis of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and polyglutamine (polyQ) diseases. Within the polyQ disease family, our lab studies Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia. It is caused by a CAG repeat expansion in ATXN3, leading to neuron loss and gliosis in disease-vulnerable brain regions. We recently uncovered an early and robust OL maturation deficit in SCA3 mice that is cell-autonomous and due to mutant ATXN3 toxic gain-of-function. Excitingly, the OL maturation deficit is biochemically, histologically, and functionally rescued by anti-ATXN3 antisense oligonucleotide (ASO) treatment. What remains unknown are the mechanisms underlying the impairment of myelinating OLs in SCA3. Surveying bulk RNAseq data from an SCA3 disease-vulnerable brain region, we found strong, but ASO- rescuable, transcriptional dysregulation of cholesterol biosynthesis in SCA3 mice. This led us to consider the contribution of lipids (including cholesterol) to the reduced population of mature, myelinating OLs in SCA3. Myelin has a high lipid content compared to other biological membranes, and we recently reported reduced myelination in disease-vulnerable brain regions of SCA3 mice and post-mortem patients. To determine if lipid dysregulation contributes to SCA3 disease, we worked with collaborators to conduct unbiased liquid chromatography-mass spectrometry-based lipidomics on the disease-vulnerable cerebellum. We found a distinct lipid profile in SCA3 mice and post-mortem patient cerebella compared to controls, including a three- fold reduction in cholesterol. To our knowledge, this is the first unbiased study of lipids in SCA3 brains. Now that we have established lipid dysregulation as a feature of SCA3 disease, we can explore its mechanistic role in the OL maturation and myelination impairment. This proposal will elucidate the contribution of lipid dysregulation via mutant ATXN3 toxic gain-of-function to the SCA3 OL maturation and myelination impairment by (1) determining the onset of myelin-specific lipid changes in SCA3 mouse models in relation to the onset of the OL maturation impairment, and (2) assessing rescue of lipid dysregulation and OL maturation/myelination when mutant ATXN3 is genetically silenced in OLs using our conditional SCA3 mouse model. These studies are expected to reveal novel contributors to SCA3 pathogenesis that may directly impact patient care. Additionally, the proposed project will enable me to develop essential skills in experimental design, data analysis, and scientific communication, preparing me for a career as an independent academic investigator focused on glial contributions to neurodegenerative disease.