Identified the causative gene for EAOH end elucidation the molecular mechanisms of neurodegeneration in EAOH

鉴定了EAOH的致病基因，阐明了EAOH神经变性的分子机制

• 批准号: 14207029
• 负责人: TSUJI Shoji
• 金额: $ 25.38万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207029/
• 关键词: spinocerebellar degeneration; DNA repair; single strand DNA break; aprataxin; ocular motor apraxia; liypoalbuminemia; cerebellum; 小脳; aprataxin; spinoxerebellar degeneration; DNA Repair; ocular motor apraxia; hypoalbuminenia; spinocerebellar

We have previously identified the causative gene for early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), an autosomal recessive neurodegenerative disease. We named the causative gene "aprataxin". This study was aimed to elucidate the molecular mechanisms of neurodegeneration in EAOH and, furthermore, to establish the therapeutic strategies for this diseases. In previous studies we showed that there are two major isoforms of aprataxin mRNA, of which we demonstrated that long form aprataxin is the component essential for its physiological function. Furthermore, we identified that aprataxin interacts with XRCC1 (X-ray repair cross complementing group 1) based on yeast two hybrid assay as well as im nuno coprecipitation experiments, raising the possibility that aprataxin has a physiological function in single strand DNA break repair (SSBR). In vitro reconstitution experiments of SSBR demonstrated that aprataxin contains 5'-phophatase as well as 3'-phophatase activities.Taken together these findings suggest that aprataxin is a new member of molecules involved in SSBR.

我们之前已经确定了早发性共济失调伴眼运动失用症和低白蛋白血症（EAOH）的致病基因，这是一种常染色体隐性神经退行性疾病。我们将致病基因命名为“aprataxin”。本研究旨在阐明EAOH神经退行性变的分子机制，并进一步建立该疾病的治疗策略。在之前的研究中，我们发现了aprataxin mRNA有两种主要的亚型，其中我们证明了长形aprataxin是其生理功能所必需的成分。此外，基于酵母双杂交实验和纳米共沉淀实验，我们发现aprataxin与XRCC1 （x射线修复交叉互补组1）相互作用，提出了aprataxin在单链DNA断裂修复（SSBR）中具有生理功能的可能性。体外重建实验表明，阿普拉西辛含有5'-磷酸酶和3'-磷酸酶活性。综上所述，这些发现表明阿普拉辛是参与SSBR的分子的新成员。

项目成果

Sano, Y., Date, H, Igarashi, S., et al.: "Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide"Ann.Neurol. 55. 241-249 (2004)

Sano, Y.、Date, H、Igarashi, S. 等人：“Aprataxin 是早发性共济失调、眼运动失用症和低白蛋白血症的致病蛋白，是一种具有潜在核苷酸作用的核蛋白”Ann.

Shimazaki, H., Takiyama, Y., et al.: "early-onset ataxia with ocular motor apraxia and hypoalbuminemia"Neurology. 59. 590-595 (2002)

Shimazaki, H., Takiyama, Y., et al.：“早发性共济失调伴眼球运动失用和低白蛋白血症”神经病学。

Shimazaki, H. et al.: "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia."Neurology. 59. 590-595 (2002)

Shimazaki, H. 等人：“早发性共济失调伴眼部运动失用和低白蛋白血症。”神经病学。

Shimazaki, H., Takiyama, Y., et al.: "early-onset ataxia with ocular motor apraxia and hypoalbuminemia."Neurology. 59. 590-595 (2004)

Shimazaki, H., Takiyama, Y., et al.：“早发性共济失调伴有眼球运动失用和低白蛋白血症。”神经病学。

Sano, Y et al.: "Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide repair protein."Ann.Neurol.. 55. 241-249 (2004)

Sano, Y 等人：“Aprataxin 是早发性共济失调、眼部运动失用症和低白蛋白血症的致病蛋白，是一种具有潜在核苷酸修复蛋白作用的核蛋白。”Ann.Neurol.. 55. 241-249