Armaan Merchant
Research Mentor(s): Hayley McLoughlin
Mentor Department:
Authors: Armaan Merchant, Alexandra F. Putka, Juan P. Mato, and Hayley S. McLoughlin
Session: Session 2 (10:00am – 10:50am)
Presentation Type: Poster 9
Abstract
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia in the world, yet no disease-modifying treatments exist. In SCA3, an expanded CAG repeat in the ATXN3 gene leads to neuron loss in disease-vulnerable brain regions, manifesting as progressive loss of motor coordination and ultimately resulting in death. To date, much of the research on SCA3 has focused on neurons as the underlying cause of disease, leaving non-neuronal cell types underexplored.
To investigate the contribution of specific cell types to SCA3 pathogenesis, we generated a novel conditional disease-off mouse model. These conditional Knock-in Q300 (cKIQ300) mice express a hyper-expanded 300 CAG repeats in the murine Atxn3 gene which can be turned off in cells expressing Cre recombinase. In this study, we leveraged cKIQ300 mice to determine the importance of neural crest-derived cells (Sox10+) to SCA3 disease phenotypes. To assess the expression pattern of Cre, we crossed cKIQ300; Sox10-Cre mice with Ai14 tdTomato mice. In 12-week-old mice, we confirmed tdTomato fluorescence in several disease-vulnerable cell types, including cerebellar Purkinje cells, oligodendrocytes, and sensory neurons of the dorsal root ganglion. Longitudinal behavioral assessments revealed that reducing mutant ATXN3 in Sox10+ cells ameliorated SCA3 motor deficits, emphasizing these cells as potential therapeutic targets.
Ongoing studies aim to narrow the investigation to individual cell types, primarily oligodendrocytes which our lab has established as key players in SCA3. We plan to use an inducible Sox10-Cre mouse model, allowing for temporal control of Cre-mediated recombination via tamoxifen administration. However, the timing of tamoxifen delivery must be optimized. Therefore, we conducted pilot studies of SOX10 expression in 8-week-old cKIQ300 mice to determine what cell types will be targeted at this timepoint. In sum, these studies provide key insights into cell-type-specific contributions to SCA3 pathogenesis that will push forward our understanding of disease mechanisms and therapeutics.
