The role of CHIP in the pathogenesis of repeat expansion diseases

Repeat expansion diseases (RENDs) are progressive neurodegenerative disorders that include spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxia 17 (SCA17). SBMA is caused by CAG expansion in the androgen receptor (AR) gene, whereas SCA17 results from CAG/CAA expansion in the TATA-binding protein (TBP) gene, leading to elongated polyglutamine (polyQ) tracts and nuclear aggregation. TBP alleles with 41–46 repeats show incomplete penetrance. The STUB1 gene, encoding the co-chaperone/E3 ligase CHIP, acts as a disease modifier, giving rise to a digenic form (SCA17-DI). CHIP promotes AR and TBP degradation, reducing aggregation. We demonstrated that CHIP mutants form inclusions and display reduced degradative activity in neuronal cells. To model these mechanisms in a patient-specific context, we generated iPSC lines from fibroblasts of a monogenic SCA17 patient, a healthy donor with an intermediate TBP allele, and a SCA17-DI patient carrying a STUB1 mutation. These lines were differentiated into neuronal precursors by small molecule protocols, providing a platform to study TBP–CHIP interactions and the effects of STUB1 mutations on protein quality control, including genes linked to chaperone-assisted autophagy (HSPA8, HSPB8, BAG3). Finally, we apply molecular approaches to assess how STUB1 mutations affect AR aggregation and degradation, further elucidating CHIP’s role as a modifier in RENDs. Supported by Fondazione Cariplo - Italy (n. 2021–1544)