Journal Article

Protein kinase Cγ, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin

Hirohide Asai, Makito Hirano, Keiji Shimada, Takao Kiriyama, Yoshiko Furiya, Masanori Ikeda, Takaaki Iwamoto, Toshio Mori, Kazuto Nishinaka, Noboru Konishi, Fukashi Udaka and Satoshi Ueno

in Human Molecular Genetics

Volume 18, issue 19, pages 3533-3543
Published in print October 2009 | ISSN: 0964-6906
Published online June 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp298
Protein kinase Cγ, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin

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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.

Journal Article.  6912 words.  Illustrated.

Subjects: Genetics and Genomics

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