Abstract
The autosomal dominant inherited spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by cerebellar atrophy and loss of Purkinje neurons. Spinocerebellar ataxia type 14 (SCA14) is a rare variant of SCAs caused by missense mutations or deletions in the PRKCG gene encoding the protein kinase C γ (PKCγ). Although mutated PKCγs are responsible for SCA14, it is still unclear exactly how mutated PKCγs are involved in SCA14 pathogenesis. Therefore, it is important to study how PKCγ signaling is altered in the cerebellum, which genes or signaling pathways are affected, and how this leads to neurological disease. In this study, we used a mouse line carrying a knock-in pseudo-substrate domain mutation in PKCγ (PKCγ-A24E) as an SCA14 model and performed RNA sequencing (RNA-seq) analysis at an early developmental timepoint (postnatal day 15) to investigate changes in the gene profile compared to wildtype mice. We analyzed both heterozygous (Het) PKCγ-A24E mice and homozygous (Homo) PKCγ-A24E mice for transcriptomic changes. The Het PKCγ-A24E mice reflects the situation observed in human SCA14 patient, while Homo PKCγ-A24E mice display stronger phenotypes with respect to Purkinje cell development and behavior. Our findings highlight an abundance of modifications affecting genes involved in developmental processes, suggesting that at least a part of the final phenotype is shaped by altered cerebellar development and is not only caused by changes in mature animals.