PATHOGENIC MECHANISM OF CONGENITAL ANOMALY AND LIFE-STYLE RELATED DISEASES BASED ON PEROXISOMAL METABOLISM

基于过氧化物酶体代谢的先天性异常及生活方式相关疾病的发病机制

• 批准号: 17591079
• 负责人: SHIMOZAWA Nobuyuki
• 金额: $ 2.24万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591079/
• 关键词: PEROXISOME; FATTY ACID β-OXIDATION; LIFE-STYLE RELATED DISEASE; SCREEN SYSTEM OF PEROXISOMAL DISEASES

(1) We have established a diagnostic system of peroxisomal diseases in Japan, and have identified 40 Japanese with peroxisomal biogenesis disorders (PBD), 11 patients with beta-oxidation enzyme deficiencies and more than 100 patients with X-linked adrenoleukodystrophy (ALD).(2) The national history of ALD was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adorescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed.(3) We demonstrated Baicalein 5,6,7-trimethyl ether, a flavonoid derivative may be a candidate for the therapeutic compound for ALD.(4) We investigated the clinical, biochemical and molecular findings, and morphology of peroxisomes in Japanese patients with peroxisomal beta-oxidation enzymes deficiencies, including acyl-CoA oxidase (AOX) or D-3-hydroxyacyl-CoA dehydratase / D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (D-BP).(5) To clarify the molecular mechanism of a temperature-sensitive (TS) phenotype in PBD, we analyzed the protein 3D-structure of a SH3 domein of PEX13 protein, whose Ile326Thr mutation demonstrated a TS phenotype in peroxisomal biogenesis. These data indicated that the Ile326 should be a core residue for folding kinetics and the substitution of the Ile326 by threonine should directly alter the kinetic equilibrium, suggesting a marked increase of the unfolded molecules when the patient had a high fever.

(1)我们在日本建立了过氧化物酶体疾病的诊断系统，并确定了40名日本人过氧化物酶体生物发生障碍（PBD），11名患者β-氧化酶缺乏症和100多名患者X-连锁肾上腺脑白质营养不良（ALD）。(2)采用基于问卷调查的全国性回顾性研究，调查了ALD的全国历史。本文分析了145例患者的临床资料，其中儿童型46例，肾上腺脊髓神经病（AMN）39例，成人型33例，粘连型14例，橄榄桥脑小脑型（OPC）13例。(3)我们证明黄芩素5，6，7-三甲基醚，黄酮衍生物可能是ALD治疗化合物的候选者。(4)我们研究了日本患者过氧化物酶体β-氧化酶缺乏症的临床、生化和分子学发现以及过氧化物酶体的形态学，包括酰基辅酶A氧化酶（AOX）或D-3-羟酰基辅酶A脱氢酶/ D-3-羟酰基辅酶A脱氢酶双功能蛋白（D-BP）。(5)为了阐明PBD中温度敏感（TS）表型的分子机制，我们分析了PEX 13蛋白的SH 3 domein的蛋白质三维结构，其Ile 326 Thr突变表明过氧化物酶体生物发生中的TS表型。这些数据表明Ile 326应该是折叠动力学的核心残基，并且Ile 326被苏氨酸取代应该直接改变动力学平衡，这表明当患者高热时未折叠分子显著增加。

项目成果

Natural history of X-linked adrenoleukodystrophy in Japan

• DOI: 10.1016/j.braindev.2004.09.008
• 发表时间: 2005-08-01
• 期刊: BRAIN & DEVELOPMENT
• 影响因子: 1.7
• 作者: Suzuki, Y;Takemoto, Y;Tsuji, S
• 通讯作者: Tsuji, S

Aberrant peroxisome morphology in peroxisomal beta-oxidation enzyme deficiencies.

过氧化物酶体β-氧化酶缺陷导致过氧化物酶体形态异常。

• 发表时间: 2006
• 期刊: Brain Dev. 28
• 作者: Funato M;Shimozawa N;Nagase T;Takemoto Y;Suzuki Y;Imamura Y;Matsumoto T;Tsukamoto T;Kojidani T;Osumi T;Fukao T;Kondo N.
• 通讯作者: Kondo N.

The common phospholipid binding activity of the N-terminal domains of PEX1, VCP/p97

PEX1、VCP/p97 N 端结构域的常见磷脂结合活性

• 发表时间: 2006
• 期刊: FEBS Journal 273
• 作者: Shiozawa K;Shimozawa N et al.
• 通讯作者: Shimozawa N et al.

Molecular mechanism of a temperature-sensitive phenotype in peroxisoma biogenesis disorder

过氧化物酶体生物发生障碍中温度敏感表型的分子机制

• 发表时间: 2005
• 期刊: Pediatr Res 58
• 作者: Hashimoto K;Shimozawa N et al.
• 通讯作者: Shimozawa N et al.

Molecular mechanism of a temperature-sensitive phenotype in peroxisome biogenesis disorders

过氧化物酶体生物发生障碍中温度敏感表型的分子机制

• 发表时间: 2005
• 期刊: Pediatr Res 58
• 作者: Hashimoto K;Shimozawa N et al.
• 通讯作者: Shimozawa N et al.