| Co-Investigator(Kenkyū-buntansha) |
NANBA Eiji Tottori University, Gene Research Center, Associate Professor, 遺伝子実験施設, 助教授 (40237631)
AKABOSHI Shinjiro Tottori University, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 講師 (90231810)
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| Research Abstract |
Ataxia-telangiectasia (AT) is caused by deficient ATM protein, exhibiting degeneration of cerebellar neurons. We investigated the function of ATM in the CNS and the mechanisms of neuronal death.
(1) We have demonstrated ATM protein is expressed in human CNS, and the expression is up-regulated during development. The distribution of ATM protein well corresponds to the lesions in AT.Thus, the spatial and temporary pattern of the ATM expression correlated with clinicopathological findings in AT, indicating that the defect of ATM is directly related to the neurodegeneration.
(2) ATM protein is localized in neuronal cytoplasma, as shown in immature Purkinje cells, and cytoplasmic ATM has been shown to be present in peroxisome. Although the cytoplasmic function of ATM remains unknown, our preliminary study suggests peroxisome dysfunction, leading to accumulation of oxidative stress and possibly neurodegeneration. Further investigations are being under way, regarding this point.
(3) AIM protein is involved in repair of DNA double-strand break (DSB). We have revealed the up-regulation of expression is not limited to ATM protein. Other proteins in DSB repair, such as DNA-dependent protein kinase catalytic subunit, Ku, NBS1 and ATR, are highly expressed immature human neurons during gestational period. These support the occurrence of DSB during neurogenesis, which has been speculated by the lethality of mutant mice severely lacking DSB repair. At this point, it remains unanswered whether the neurodegeneration in AT is related to the defective repair of DSB in cerebellar cortical neurons during development. Although AT mutant mice have been developed in several laboratories, cerebellar ataxia has not been observed, and a model mouse of AT is not available. Thus, we are going to perform further investigation in vitro system, using cultured neurons.
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