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 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.
Asai
Hirohide
H
Department of Neurology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
Hirano
Makito
M
Shimada
Keiji
K
Kiriyama
Takao
T
Furiya
Yoshiko
Y
Ikeda
Masanori
M
Iwamoto
Takaaki
T
Mori
Toshio
T
Nishinaka
Kazuto
K
Konishi
Noboru
N
Udaka
Fukashi
F
Ueno
Satoshi
S
D021581:Active Transport, Cell Nucleus; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010766:Phosphorylation; D011493:Protein Kinase C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C087857:protein kinase C gamma; D011493:Protein Kinase C