PAQR7 IS AN UPSTREAM REGULATOR OF PKCΓ INVOLVED IN THE REGULATION OF PURKINJE CELL DENDRITIC MORPHOLOGY IN SCA14

Purkinje cells (PCs) shape cerebellar circuits for motor and cognitive function, and their dendritic architecture is tightly regulated during development. In spinocerebellar ataxia type 14 (SCA14), caused by mutations in protein kinase C gamma (PKCγ), disruption of PC morphology leads to an ataxic phenotype. Although PKCγ regulates multiple signalling pathways involved in dendritic development, its upstream regulators remain less well defined. Here, we investigated the regulation of PKCγ expression and activity using a mutant mouse model (PKCγ-A24E) expressing a constitutively active form of PKCγ, leading to impaired PC dendritic growth and cerebellar dysfunction. Based on RNA-sequencing studies in PKCγ-A24E mice, we identified Progestin and adipoQ receptor family member 7 (Paqr7) as being significantly downregulated compared to wild-type controls. Upon overexpression, Paqr7 localizes to the Golgi apparatus of PCs and promotes PKCγ overexpression and hyperactivation, resulting in disrupted PC dendritic morphology, while Paqr7 knockdown does not affect dendritic architecture. These findings suggest that Paqr7 acts upstream of PKCγ and that its downregulation in SCA14 may reflect a compensatory feedback mechanism limiting PKCγ overactivation. Additional mechanistic insights into Paqr7- PKCγ interactions will be discussed at the meeting. Together, our results identify Paqr7 as a novel regulator of PKCγ expression with an impact on PC dendritic development, implicating it also in SCA14 pathogenesis.