A New Mouse Model Related To Sca14 Carrying A Pseudosubstrate Domain Mutation In Pkc Gamma Shows Perturbed Purkinje Cell Maturation And Ataxic Motor Behavior

Spinocerebellar ataxias (SCAs) are diseases characterized by cerebellar atrophy and loss of Purkinje neurons caused by mutations in diverse genes. In SCA14, the disease is caused by point mutations or small deletions in protein kinase C gamma (PKC gamma), a crucial signaling protein in Purkinje cells. It is still unclear whether increased or decreased PKC gamma activity may be involved in the SCA14 pathogenesis. In this study, we present a new knock-in mouse model related to SCA14 with a point mutation in the pseudosubstrate domain, PKC gamma-A24E, known to induce a constitutive PKC gamma activation. In this protein conformation, the kinase domain of PKC gamma is activated, but at the same time the protein is subject to dephosphorylation and protein degradation. As a result, we find a dramatic reduction of PKC gamma protein expression in PKC gamma-A24E mice of either sex. Despite this reduction, there is clear evidence for an increased PKC activity in Purkinje cells from PKC gamma-A24E mice. Purkinje cells derived from PKC gamma-A24E have short thickened dendrites typical for PKC activation. These mice also develop a marked ataxia and signs of Purkinje cell dysfunction making them an interesting new mouse model related to SCA. Recently, a similar mutation in a human patient was discovered and found to be associated with overt SCA14. RNA profiling of PKC gamma-A24E mice showed a dysregulation of related signaling pathways, such as mGluR1 or mTOR. Our results show that the induction of PKC gamma activation in Purkinje cells results in the SCA-like phenotype indicating PKC activation as one pathogenetic avenue leading to a SCA.