Protein kinase C[gamma], a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase Cγ (PKCγ). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with increased kinase activity. Notably, one patient with a severe phenotype is the first homozygote for the mutation causing SCA14. We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (APTX), a DNA repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant PKCγ, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin α, a nuclear import adaptor. Decreased nuclear APTX increased oxidative stress-induced DNA damage and cell death. Phosphorylation-resistant APTX, kinase inhibitors, and antioxidants may be therapeutic options for SCA14.