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

• Project/Area Number: 14570746
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tottori University
• Principal Investigator: NANBA Eiji (2004) TOTTORI UNIVERSITY, RESEARCH CENTER FOR BIOSCIENCE AND TECHNOLOGY, PROFESSOR, 生命機能研究支援センター, 教授 (40237631); 岡 明 (2002-2003) 鳥取大学, 医学部, 助教授 (00251273)
• Co-Investigator(Kenkyū-buntansha): INOUE Takehiko TOTTORI UNIVERSITY, INSTITUTE OF NEUROLOGICAL SCIENCES, ASSISTANT PROFESSOR, 医学部附属病院, 助手 (80346361) ; 難波 栄二 鳥取大学, 生命機能研究支援センター, 教授 (40237631) ; 赤星 進二郎 鳥取大学, 医学部, 講師 (90231810)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 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

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.

Research Products

• [Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na(+) channel blocker aprindine. (2005)
  • Author(s): Tanaka H et al.
  • Journal Title: Biochem Biophys Res Commun. 331 Pages: 1001-1006
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A non-NF2 case of schwannomas of vestibular and trigeminal nerves with different mutations of NF2 gene. (2005)
  • Author(s): Kambe A et al.
  • Journal Title: Surg Neurol 63 Pages: 62-65
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A non-NF2 case of schwannomas of vestibular and trigeminal nerves with different mutations of NF2 gene. (2005)
  • Author(s): Kambe A, Kamitani H, Watanabe T, Oka A, Inagaki H, Ishii T, Ueki K.
  • Journal Title: Surg Neurol 63 Pages: 62-65
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • 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
• [Journal Article] N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells : a potential chemical chaperone therapy (2004)
  • Author(s): Lin H et al.
  • Journal Title: Biochim Biophys Acta 1689 Pages: 219-228
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients. (2004)
  • Author(s): Yamamoto T et al.
  • Journal Title: Brain Dev 26・4 Pages: 245-250
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1) (2004)
  • Author(s): Torisu Y et al.
  • Journal Title: Am J Med Genet 131A Pages: 94-98
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy. (2004)
  • Author(s): Nakada C et al.
  • Journal Title: Pathobiology 71 Pages: 43-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. (2004)
  • Author(s): Kato M et al.
  • Journal Title: Hum Mutat 23 Pages: 147-159
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: Hum Mutat 23 Pages: 147-159
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy. (2004)
  • Author(s): Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.
  • Journal Title: Pathobiology 71 Pages: 43-51
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1). (2004)
  • Author(s): Torisu Y, Yamamoto T, Fujiwaki T, Kadota M, Oshimura M, Kurosawa K, Akaboshi S, Oka A.
  • Journal Title: Am J Med Genet 131A(1) Pages: 94-98
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Biochimica et Biophysica Acta 1689 Pages: 219-228
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients. (2004)
  • Author(s): Yamamoto T, Feng JH, Higaki K, Taniguchi M, Nanba E, Ninomiya H, Ohno K.
  • Journal Title: Brain Dev. 26(4) Pages: 245-250
  • NAID: 10020552645
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease. (2004)
  • Author(s): Lin H et al.
  • Journal Title: Biochim Biophys Acta 1689 Pages: 219-228
• [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients. (2004)
  • Author(s): Yamamoto T et al.
  • Journal Title: Brain Dev.2004 26・4 Pages: 245-250
• [Journal Article] Chemical chaperone therapy for brain pathology in GM1-gangliosidosis. (2003)
  • Author(s): Matsuda J et al.
  • Journal Title: Proc Natl Acad Sci U S A 100 Pages: 15912-15917
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components. (2003)
  • Author(s): Ogura K et al.
  • Journal Title: Neuropediatrics 34 Pages: 307-310
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] New GAA mutations in Japanese patients with GSDII (Pompe disease). (2003)
  • Author(s): Pipo JR et al.
  • Journal Title: Pediatr Neurol 29 Pages: 284-287
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy. (2003)
  • Author(s): Nakada C et al.
  • Journal Title: Pathol Int 53 Pages: 653-658
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cardiac-restricted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy. (2003)
  • Author(s): Nakada C et al.
  • Journal Title: Lab Invest 83 Pages: 711-719
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Myelin transcription factor 1(Myt1) immunoreactivity in infants with periventricular leukomalacia. (2003)
  • Author(s): Hirayama A et al.
  • Journal Title: Dev Brain Res 140 Pages: 85-92
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Myelin transcription factor 1 (Myt1) immunoreactivity in infants with periventricular leukomalacia. (2003)
  • Author(s): Hirayama A, Oka A, Ito Masayuki, Tanaka F, Ohkoshi Y, Takashima S.
  • Journal Title: Dev Brain Res 140 Pages: 85-92
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardiac-restrcted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy. (2003)
  • Author(s): Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda I, Sato K, Mori S, Ito H, Moriyama M.
  • Journal Title: Lab Invest 83 Pages: 711-719
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy. (2003)
  • Author(s): Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.
  • Journal Title: Pathol Int 53 Pages: 653-658
  • NAID: 50000346440
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Pediatr Neurol 29 Pages: 284-287
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components. (2003)
  • Author(s): Ogura K, Oka A, Ohno K.
  • Journal Title: Neuropediatrics 34 Pages: 307-310
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • 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
• [Journal Article] Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection. (2002)
  • Author(s): Ueno M et al.
  • Journal Title: Brain Dev 24 Pages: 106-108
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection. (2002)
  • Author(s): Ueno M, Oka A, Koeda T, Okamoto R, Takeshita K.
  • Journal Title: Brain Dev 24 Pages: 106-108
  • NAID: 10010103555
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
• [Publications] Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda I, Sato K, Mori S, Ito H, Moriyama M.: "Cardiac-restrcted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy."Lab Invest. 83巻. 711-719 (2003)
• [Publications] Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.: "Cardiac ankyrin repeat protein is preferentially induced in atrophic my ofibers of congenital myopathy and spinal muscular atrophy."Pathol Int. 53巻. 653-658 (2003)
• [Publications] Ogura K, Oka A, Ohno K.: "Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components."Neuropediatrics. 34巻. 307-310 (2003)
• [Publications] 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)
• [Publications] Hirayama A, Oka A, Ito M, Tanaka F, Ohkoshi Y, Takashima S: "Myelin transcription factor 1 (Myt1) immunoreactivity in infants with periventricular leukomalacia"Developmental Brain Research. 140巻. 85-92 (2003)
• [Publications] 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).
• [Publications] Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito M, Moriyama M: "Cardial onkyrin reperted protein is induced in atrophic nyofibers of conquenital myoparhy and spinal muscular atrophy"Laboratory Investigation. (in press).
• [Publications] Shiroma, N.Kanazawa, Z.Kato, N.Shimozawa, A.Imamura, M.Ito, K.Ohtani, A.Oka, K.Wakabayashi, M.Iai, K.Sugai, M.Sasaki, M.Kaga, T.Ohta, S.Tsujino: "Molecular genetic study in Japanese patients with Alexander disease: a novel mutation, R79L"Brain and Development. 25. 116-121 (2003)
• [Publications] Takaura N, Yagi T, Maeda M, Nanba E, Matsuda J, Oshima A, Suzuki Y, Yamano T, Yanaka T: "Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene"Gene Therapy. (in press).
• [Publications] Saito Y, Suzuki K, Nanba E, Yamamoto T, Ohno K, Murayama S: "Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apoliporotein Ee4 homozygosity"Annol Neurology. 52. 351-355 (2002)