Host: The Japan Radiation Research Society, Chairman of the 52nd Annual Meeting, Toshiteru Okubo (Radiation Effects Research Foundation)
Aprataxin is a protein causative for autosomal recessive ataxia that occurs most commonly in Japan. We previously found that aprataxin has an enzymatic activity and that mutants lose their activities. Further experiments using aprataxin knock-down cells, patient cells, and patient cerebellum demonstrate that this protein is involved in vivo in repair of oxidative stress-induced DNA single strand break (SSB). Other researchers demonstrated that aprataxin catalyzes removal of 5’-AMP and 3’-phosphate at SSB, suggesting that this protein plays an important role in SSB repair.
We then identified impaired nuclear import of aprataxin in an autosomal recessive disease, triple A syndrome. This disease shares some neurologic features with amyotrophic lateral sclerosis, but infrequently shows ataxia. Other symptoms include esophageal achalasia, alacrima, and adrenal insufficiency. The causative protein is ALADIN, a component of nuclear pore complex. In triple A syndrome oxidative stress increased DNA damage and cell death along with decreased nuclear aprataxin.
Further research demonstrates that nuclear import of aprataxin is regulated by its phosphorylation. Protein kinase C gamma, a protein causative for autosomal dominant cerebellar ataxia type 14 (SCA14), phosphorylates aprataxin at the residue near nuclear localization signal, and disturbed the nuclear import. A PKC inhibitor increased nuclear aprataxin, DNA repair capacity, and cell survival.
In conclusion, these findings demonstrate that qualitative and quantitative alterations in the DNA repair protein aprataxin are associated with neurological diseases and that oxidative stress causes accumulation of DNA damage leading to neurodegeneration.