2004 Fiscal Year Final Research Report Summary
THE RESEARCH OF THE THERAPY FOR GAUCHER DISEASE WITH CENTRAL NERVOUS INVOLVEMENT BY THE LOW MOLECULAR COMPOUNDS.
| Project/Area Number |
14570746
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tottori University |
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Principal Investigator |
NANBA Eiji TOTTORI UNIVERSITY, RESEARCH CENTER FOR BIOSCIENCE AND TECHNOLOGY, PROFESSOR, 生命機能研究支援センター, 教授 (40237631)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Takehiko TOTTORI UNIVERSITY, INSTITUTE OF NEUROLOGICAL SCIENCES, ASSISTANT PROFESSOR, 医学部附属病院, 助手 (80346361)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Gaucher disease / Therapy / Low molecular compound / Carba-sugar / Lysosome |
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| Research Abstract |
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.
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Research Products
(28 results)
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[Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na(+) channel blocker aprindine.2005
Author(s)
Tanaka H, Miake J, Notsu T, Sonyama K, Sasaki N, Iitsuka K, Kato M, Taniguchi S, Igawa O, Yoshida A, Shigemasa C, Hoshikawa Y, Kurata Y, Kuniyasu A, Nakayama H, Inagaki N, Nanba E, Shiota G, Morisaki T, Ninomiya H, Kitakaze M, Hisatome I.
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Journal Title
Biochem Biophys Res Commun. 331(4)
Pages: 1001-1006
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.2004
Author(s)
Kato M, Das S, Petras K, Kitamura K, Morohashi K, Abuelo DN, Barr M, Bonneau D, Brady A, Carpenter NJ, Frisone F, Fukuda T, Guerrini R, Iida E, Itoh M, Lewanda AF, Nanba Y, Oka A, Proud VK, Russel KL, Saugier-Veber P, Schelley SL, Selicorni A, Shaner R, Silengo M, Stewart F, Sugiyama N, Toyama J, Toutain A, Vargas AL, Yanazawa M, Zackai EH, Dobyns WB.
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Journal Title
Hum Mutat 23
Pages: 147-159
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease.2004
Author(s)
Lin H, Sugimoto Y, Ohsaki Y, Ninomiya H, Oka A, Taniguchi M, Ida H, Eto Y, Ogawa S, Matsuzaki Y, Sawa M, Inoue T, Higaki K, Nanba E, Ohno K, Suzuki Y.
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Journal Title
Biochimica et Biophysica Acta 1689
Pages: 219-228
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] New GAA mutations in Japanese patients with GSDII (Pompe disease).2003
Author(s)
Pipo JR, Feng JH, Yamamoto T, Ohsaki Y, Nanba E, Tsujino S, Sakuragawa N, Martiniuk F, Ninomiya H, Oka A, Ohno K.
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Journal Title
Pediatr Neurol 29
Pages: 284-287
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis.2003
Author(s)
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.
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Journal Title
Proc Natl Acad Sci USA. 100(26)
Pages: 15912-15917
Description
「研究成果報告書概要(欧文)」より
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