PhD Student The Hebrew University of Jerusalem Jerusalem, Yerushalayim, Israel
Abstract: Polyglutamine (polyQ) diseases are a group of nine neurodegenerative disorders caused by the expansion of CAG trinucleotide repeats in specific genes, leading to toxic polyglutamine tracts in the encoded proteins. While their genetic basis is well-established, the molecular mechanisms driving selective neuronal vulnerability remain elusive. Emerging evidence highlights aging and epigenetic dysregulation as critical factors in polyQ disease progression. Spinocerebellar ataxia types 3 (SCA3) and 6 (SCA6) are two polyQ diseases characterized by spinocerebellar ataxias but differ in the functions and expression patterns of the affected proteins, ATXN3 and α1ACT, respectively. These differences, along with shared pathological features, make them ideal models for comparative analysis. In this study, we use stem cells to generate cerebellar brain organoids and investigate the normal and mutant roles of ATXN3 and α1ACT in disease progression. Specifically, we examine their involvement in epigenetic regulation across developmental stages, from stem cells to mature neurons. By identifying shared and disease-specific mechanisms, our work provides novel insights into the molecular mechanism of polyQ disorders. Together, our findings illuminate key molecular pathways driving neurodegeneration in polyQ diseases, offering potential targets for therapeutic interventions that address these debilitating conditions.
