Unraveling the Interaction between TBP and STUB1 in the Pathogenesis of SCA17-DI

Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease characterized by a range of neurologic and psychiatric symptoms. The etiology of SCA17 involves dysfunction and loss of neuronal cells, particularly affecting Purkinje cells. The key factor contributing to disease development is the length of the variable CAG/CAA triplet repeats in the coding sequence of the TATA-box binding protein (TBP) gene. In the general population alleles with up to 41 repeats are prevalent, while expansions beyond 47 repeats are associated with full penetrance. At the protein level, pathogenic alleles are characterized by the presence of polyglutamine expansions, which lead to the formation of nuclear aggregates. In individuals with alleles containing 41-46 repeats, incomplete penetrance has been observed. In those cases, the contribution of a heterozygous mutation in the STUB1 gene was found to be important, resulting in a digenic variant of SCA17 (SCA17-DI). STUB1 encodes the E3 ubiquitin ligase CHIP, which is thought to be involved in the proteasomal degradation of the TBP protein. To further investigate the pathomechanism underlying SCA17-DI, we developed iPSC lines derived from fibroblasts from donors with different genetic backgrounds: a patient with the monogenic form of SCA17, a healthy donor with an intermediate TBP allele, and a patient with SCA17-DI carrying a mutation in STUB1. These iPSC lines, along with healthy control, are subsequently differentiated into Purkinje cells. This disease model allows us to study the interaction between TBP and STUB1 involved in the pathogenesis of SCA17-DI. Furthermore, preliminary results of gene expression analysis related to protein homeostasis and autophagy suggest putative disease-related changes in patient-derived primary cell lines. Funding: Fondazione Cariplo - Italy (n. 2021–1544)