THE RESEARCH OF THE THERAPY FOR GAUCHER DISEASE WITH CENTRAL NERVOUS INVOLVEMENT BY THE LOW MOLECULAR COMPOUNDS.

低分子化合物治疗中枢神经受累戈谢病的研究。

• 批准号: 14570746
• 负责人: NANBA Eiji
• 金额: $ 2.3万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570746/
• 关键词: Gaucher disease; Therapy; Low molecular compound; Carba-sugar; Lysosome; 分子シャペロン; β-グルコセレブロシダーゼ; 分子シャペロン療法; ライソゾーム病; 先天代謝異常

Gaucher disease(GD) is the most common form of sphingolipidosis and is caused by a defect of beta-glucosidase (beta-Glu). A carbohydrate mimic N-octyl-beta-valienamine(NOV) is an inhibitor of beta-Glu. When applied to cultured GD fibroblasts with F213I beta-Glu mutation, NOV increased the protein level of the mutant enzyme and up-regulated cellular enzyme activity. The maximum effect of NOV was observed in F213I homozygous cells in which NOV treatment at 30 microM for 4 days caused a approximately 6-fold increase in the enzyme activity, up to approximately 80% of the activity in control cells. NOV was not effective in cells with other beta-Glu mutations, N370S,L444P,84CG and RecNciI. Immunofluorescence and cell fractionation showed localization of the F213I mutant enzyme in the lysosomes of NOV-treated cells. Consistent with this, NOV restored clearance of 14C-labeled glucosylceramide in F213I homozygous cells. F213I mutant beta-Glu rapidly lost its activity at neutral pH in vitro and this pH-dependent loss of activity was attenuated by NOV. These results suggest that NOV works as a chemical chaperone to accelerate transport and maturation of F213I mutant beta-Glu and may suggest a therapeutic value of this compound for GD.

戈谢病（GD）是最常见的鞘脂病形式，由β-葡萄糖苷酶（β-Glu）缺陷引起。碳水化合物模拟物N-辛基-β-维列胺（NOV）是β-Glu的抑制剂。当应用于培养的具有F213 I β-Glu突变的GD成纤维细胞时，NOV增加了突变酶的蛋白水平并上调了细胞酶活性。在F213 I纯合细胞中观察到NOV的最大效应，其中30 μ M NOV处理4天导致酶活性增加约6倍，高达对照细胞中活性的约80%。NOV在具有其他β-Glu突变N370 S、L444 P、84 CG和RecNciI的细胞中无效。免疫荧光和细胞分级显示F213 I突变酶在经NOV处理的细胞的溶酶体中的定位。与此一致，NOV恢复了F213 I纯合细胞中14 C标记的葡萄糖神经酰胺的清除。F213 I突变体β-Glu在体外中性pH下迅速失去活性，NOV可减弱这种pH依赖性活性丧失。这些结果表明，NOV可作为化学伴侣加速F213 I突变体β-Glu的转运和成熟，并可能表明该化合物对GD的治疗价值。

项目成果

Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.: "Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy."Pathobiology. 71巻. 43-51 (2004)

Nakada C、Tsukamoto Y、Oka A、Nonaka I、Sato K、Mori S、Ito H、Moriyama M.：“肌营养不良症、先天性肌病和脊髓性肌萎缩症患者骨骼肌中 ARPP 蛋白的表达改变。”第 71 卷 43-51 (2004)

Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M: "Altered expression of ARPP protein in skeletal muscles of patient with museular dystrophy, dongenital myopathy and spinal muscular atrophy"Pathobiology. (in press).

Nakada C、Tsukamoto Y、Oka A、Nonaka I、Sato K、Mori S、Ito H、Moriyama M：“肌肉萎缩症、生殖器肌病和脊髓性肌萎缩症患者骨骼肌中 ARPP 蛋白表达的改变”病理生物学。

N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease.

N-辛基-β-缬烯胺上调培养细胞中 F213I 突变型 β-葡萄糖苷酶的活性：一种潜在的戈谢病化学伴侣疗法。

• 发表时间: 2004
• 期刊: Biochim Biophys Acta 1689
• 作者: Lin H et al.

Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection.

水痘带状疱疹病毒感染后大脑中动脉的单侧闭塞。

• 发表时间: 2002
• 期刊: Brain Dev 24
• 作者: Matsuda J;Suzuki O;Oshima A;Yamamoto Y;Noguchi A;Takimoto K;Itoh M;Matsuzaki Y;Yasuda Y;Ogawa S;Sakata Y;Nanba E;Higaki K;Ogawa Y;Tominaga L;Ohno K;Iwasaki H;Watanabe H;Brady RO;Suzuki Y.;Ueno M et al.
• 通讯作者: Ueno M et al.

Pipo JR, Feng JHa N, Martiniuk F, Ninomiya H, Oka A, Oh, Yamamoto T, Ohsaki Y, Nanba E, Tsujino S, Sakuragawno K.: "New GAA mutations in Japanese patients with GSDII (Pompe disease)."Pediatr Neurol. 29巻. 284-287 (2003)

Pipo JR、Feng JHa N、Martiniuk F、Ninomiya H、Oka A、Oh、Yamamoto T、Ohsaki Y、Nanba E、Tsujino S、Sakuragawno K.：“日本 GSDII（庞贝病）患者中的新 GAA 突变。”Pediatr神经醇。29。284-287（2003）