Gene expression profile of Purkinje cells in Kcnd3 F227del mice

Spinocerebellar ataxia type 22 (SCA22) caused by KCND3 mutations is an autosomal dominant disorder. We establish a mouse model carrying the Kcnd3 F227del mutation to study the molecular pathogenesis. Four findings are pinpointed. Firstly, the heterozygous mice exhibit an early onset of defects in motor coordination and balance, which mirror the SCA22 patients. The degeneration and a minor loss of Purkinje cells together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the Kcnd3 F227del mutant protein. Secondly, the mutant protein is retained by the endoplasmic reticulum and Golgi leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage to Golgi is the earliest manifestation. Thirdly, transcriptomic analysis revealed that the Kcnd3 F227del mutation down-regulates a panel of genes involved in the functioning of synapse and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes are detectable in knockout mice carrying a loss-of-function Kcnd3 mutation. Thus, the Kcnd3 F227del is a dominant-negative mutation. Additionally, this mouse model can serve as a pre-clinical model for exploring therapeutic strategies to treat patients.