| First Author | Shimobayashi E | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 9 | Pages | 2053-2068 |
| PubMed ID | 33478986 | Mgi Jnum | J:305637 |
| Mgi Id | MGI:6509732 | Doi | 10.1523/JNEUROSCI.1946-20.2021 |
| Citation | Shimobayashi E, et al. (2021) A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCgamma Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior. J Neurosci 41(9):2053-2068 |
| abstractText | 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 (PKCgamma), a crucial signaling protein in Purkinje cells. It is still unclear whether increased or decreased PKCgamma 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, PKCgamma-A24E, known to induce a constitutive PKCgamma activation. In this protein conformation, the kinase domain of PKCgamma 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 PKCgamma protein expression in PKCgamma-A24E mice of either sex. Despite this reduction, there is clear evidence for an increased PKC activity in Purkinje cells from PKCgamma-A24E mice. Purkinje cells derived from PKCgamma-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 PKCgamma-A24E mice showed a dysregulation of related signaling pathways, such as mGluR1 or mTOR. Our results show that the induction of PKCgamma activation in Purkinje cells results in the SCA-like phenotype indicating PKC activation as one pathogenetic avenue leading to a SCA.SIGNIFICANCE STATEMENT Spinocerebellar ataxias (SCAs) are hereditary diseases affecting cerebellar Purkinje cells and are a one of neurodegenerative diseases. While mutation in several genes have been identified as causing SCAs, it is unclear how these mutations cause the disease phenotype. Mutations in PKCgamma cause one subtype of SCAs, SCA14. In this study, we have generated a knock-in mouse with a mutation in the pseudosubstrate domain of PKCgamma, which keeps PKCgamma in the constitutive active open conformation. We show that this mutation leading to a constant activation of PKCgamma results in a SCA-like phenotype in these mice. Our findings establish the constant activation of PKC signaling as one pathogenetic avenue leading to an SCA phenotype and a mechanism causing a neurodegenerative disease. |
