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

Abstract:

:Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C gamma (PKC gamma). 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 PKC gamma, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin alpha, 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_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Asai H,Hirano M,Shimada K,Kiriyama T,Furiya Y,Ikeda M,Iwamoto T,Mori T,Nishinaka K,Konishi N,Udaka F,Ueno S

doi

10.1093/hmg/ddp298

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

3533-43

issue

19

eissn

0964-6906

issn

1460-2083

pii

ddp298

journal_volume

18

pub_type

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