Polyglutamine (
polyQ) diseases comprise
Huntington's disease and several subtypes of
spinocerebellar ataxia, including
spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded
polyQ domain-containing disease
proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular
protein clearance pathways, the activity of the
ubiquitin-
proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic
proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of
polyQ diseases.
Ubiquitin (Ub) E3
ligases catalyze the transfer of a Ub tag to label
proteins destined for proteasomal clearance. In this study, we identified an
E3 ligase,
pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded
ataxin-3 (ATXN3-polyQ), disease
protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ
protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ
protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ
protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the
E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated
protein ubiquitination pathway in SCA3 pathogenesis.