Molecular pathogenesis of familial encephalopathy with neuroserpin inclusion bodies

• Project/Area Number: 18590285
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Toyama
• Principal Investigator: HIRAGA Koichi University of Toyama, 大学院・医学薬学研究部, 教授 (40004733)
• Co-Investigator(Kenkyū-buntansha): KATO Ichiro 富山大学, 大学院・医学薬学研究部, 准教授 (50250741) ; KAWAGUCHI Hiroshi 富山大学, 大学院・医学薬学研究部, 助教 (50361952)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,200,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: 変異ニューロセルピン / 免疫電顕 / 封入体形成機構 / 小胞体 / リソゾーム / 早期発症型認知症 / ニューロセルピン / 遺伝子変異 / カイニン酸 / 免疫電子顕微鏡 / 遺伝子導入マウス / リソソーム / 封入体 / カイニン酸誘導性痙攣 / PAS陽性 / 封入体の形成部位 / トランスジェニックマウス / G392E変異 / 神経細胞 / 変異タンパク質蓄積 / 神経変性疾患 / 疾患モデル

Research Abstract

変異型神経特異的セリンプロテアーゼインヒビタ=(ニューロセルピン)は家族性ニューロセルピン封入体脳症の原因となる。数種の変異型ヒトニューロセルピンが知られているが、今回、人では最も劇症型を起こすと言われるG392Eニューロセルピンをニューロンでのみ発現するトランスジェニックマウスを作製し、変異型ニューロセルピンのニューロン内蓄積機構とその結果起こるニューロンの機能障害の原因を追及した。その結果、変異型ニューロセルピンは発現量、変異部位、加齢に依存してニューロン小胞体とリソゾームに蓄積し、代謝分解量を超える合成量が有れば、加齢と共に病的変化を起こすことを明らかにした。

Research Products

• [Journal Article] Genomic organization of regions that regulate chicken glycine decarboxylase gene transcription: physiological and pathological implications (2009)
  • Author(s): Kawaguchi H., Okamoto, S., Sikdar, D., Kume, A., Li. F., Mohafez, O.M.M., Shehata, M.H., and Hiraga, K
  • Journal Title: Gene 432 Pages: 7-18
  • Peer Reviewed
• [Journal Article] Genomic organization of regions that regulate chicken glycine decarboxylase gene transcription : physiological and pathological implications (2009)
  • Author(s): Kawaguchi H.
  • Journal Title: Gene 432 Pages: 7-18
  • Peer Reviewed
• [Journal Article] Glycine cleavage system : reaction mechanism, physiological significance, and hyperglycinemia (2008)
  • Author(s): Kikuchi, G., Motokawa, Y., Yoshida, T., and Hiraga, K
  • Journal Title: Proc. JPN. Acad., Ser. B 84 Pages: 246-263
  • NAID: 130000093931
  • Peer Reviewed
• [Journal Article] A novel model of insulin-dependent diabetes with renal and retinal lesions by transgenic expression of CaMKII (Thr286Asp) in pancreatic -cells. Diabetes Metab (2008)
  • Author(s): Kato I., Oya, T., Suzuki, H., Takasawa, K., Ichsan, A.M., Nakada, S., Ishii, Y., Shimada, Y., Sasahara, M., Tobe, K., Takasawa, S., Okamoto, H., Hiraga, K
  • Journal Title: Res. Rev 24 Pages: 486-497
  • Peer Reviewed
• [Journal Article] Mutation-, aging-, and gene dosage-dependent accumulation of neuroserpin (G392E) in endoplasmic reticula and lysosomes of neurons in transgenic mice (2008)
  • Author(s): Takasawa, A., Kato, I., Takasawa, K., Ishii, Y., Yoshida, T., Shehata, M.H., Kawaguchi, H.,Mohafez, O.M.M., Sasahara, M., and Hiraga, K
  • Journal Title: J. Biol. Chem 283 Pages: 35606-35613
  • Peer Reviewed
• [Journal Article] Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice (2008)
  • Author(s): Nakanishi, Y., Tsuneyama, K., Nomoto, K., Fujimoto, M., Salunga, T.L., Nakajima, T., Miwa, S., Murai,Y., Hayashi, S., Kato, I., Hiraga, K., Hsu, D.K., Liu, F-T., and Takano, Y
  • Journal Title: Hepatol. Res 38 Pages: 1241-152
  • NAID: 10023920841
  • Peer Reviewed
• [Journal Article] Novel transcript profiling of diffuse alveolar damage induced by hyperoxia exposure in mice: normalization by glyceraldehydes-3 phosphate dehydrogenase (2008)
  • Author(s): Shimada, I., Matsui, K., Brinkmann, B., Hoh,o.ff., .C., Hiraga, K., Tabuchi, Y., Takasaki, I., Kato, I., Kawaguchi, H., Takasawa, K., Iida, R., Takizawa, H., Matsuki, T
  • Journal Title: Int. J. Legal Med 122 Pages: 373-383
  • NAID: 120001296353
  • Peer Reviewed
• [Journal Article] Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorigenesis: an oligonucleotide microarray studyJ (2008)
  • Author(s): Abdel-Aziz H. O., Murai, Y., Takasaki, I., Tabuchi, Y., Zheng, H-C., Nomoto, K., Takahashi, H., Tsuneyama, K., Kato, I., Hsu, D.K., Liu, F-T., Hiraga, K., and Takano, Y
  • Journal Title: Cancer Res. Clin. Oncol 134 Pages: 777-788
  • Peer Reviewed
• [Journal Article] Mutation-, aging-, and gene dosage-dependent accumulation of neuroserpin (G392E) in endoplasmic reticula and lysosomes of neurons in transgenic mice. (2008)
  • Author(s): Takasawa A.
  • Journal Title: J. Biol. Chem. 283 Pages: 35606-35613
  • Peer Reviewed
• [Journal Article] Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice. (2008)
  • Author(s): Liu H-X.
  • Journal Title: Neurosci. Lett 448 Pages: 67-70
  • Peer Reviewed
• [Journal Article] Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice. (2008)
  • Author(s): Nakanlshi Y.
  • Journal Title: Hepatol Res. 38 Pages: 1241-1521
  • Peer Reviewed
• [Journal Article] Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorisenesis : an oligonucleotide microarray study. (2008)
  • Author(s): Abdel-Aziz H. O.
  • Journal Title: J. Cancer Res. Clin. Oncol. 134 Pages: 777-788
  • Peer Reviewed
• [Journal Article] A novel mode1 of insulin-dependent diabetes with renal and retinal lesions by transgenic expression of CaMKIIα (Thr286Asp)in pancreatic β-cells. (2008)
  • Author(s): Kato I.
  • Journal Title: Diabetes Metab. Res. Rev. 24 Pages: 486-497
  • Peer Reviewed
• [Journal Article] Glycine cleavage system:reaction mechanism, physiological significance, and hyperglycinemia (2008)
  • Author(s): Kikuchi, G.
  • Journal Title: Proc.JPN Acad. Ser. B
  • Peer Reviewed
• [Journal Article] Novel transcript profiling of diffuse alveolar damage induced by hyperoxia exposure in mice: normalization by glyceraldehyde 3-phosphate dehydrogenase (2008)
  • Author(s): Shimada I.
  • Journal Title: Int. J. Legal Med
  • Peer Reviewed
• [Journal Article] Transcriptional modulation by nuclear matrix protein P130/MAT3 associated with MAR/SAR. (2007)
  • Author(s): Hibino, Y., Usui, T., & Hiraga, K
  • Journal Title: In Nuclear Dynamics, Nagata, K., & Takeyasu, K. eds Pages: 255-262
  • Peer Reviewed
• [Journal Article] Neuroprotective role of transgenic PAF-acetyl hydrolase II in mouse models of focal cerebral ischemia (2007)
  • Author(s): Umemura, K., Kato, I., Hirashima, Y., Ishii, Y., Inoue, T., Aoki, J., Kono, K., Oya, T., Hayashi, N., Hamada, H., Endo, S., Oda, M., Arai, H., Kinouchi, H., and Hiraga, K
  • Journal Title: Stroke 38 Pages: 1063-1068
  • Peer Reviewed
• [Journal Article] Transcriptional modulation by nuclear matrix protein P130/MAT3 associated with MAR/SAR. (2007)
  • Author(s): Hibino, Y.
  • Journal Title: In Nuclear Dynamics, Nagata, K., & Takeyasu, K. eds., pp.255-262, Springer, New York Pages: 255-262
  • Peer Reviewed
• [Journal Article] Neuroprotective role of transgenic PAF-acetyl hydrolase ll in mouse models of focal cerebral ischemia (2007)
  • Author(s): Umemura, K.
  • Journal Title: Stroke 38 Pages: 1063-1068
  • Peer Reviewed
• [Journal Article] CD38 is critical for social behaviour by regulating oxytocin secretion. (2007)
  • Author(s): Jin D.
  • Journal Title: Nature (in press)
• [Journal Article] Connection between a dural artery and a dural vein in a dural arteriovenous fistula of the cranial vault. (2007)
  • Author(s): Hori F.
  • Journal Title: Neurol. Med. Chir.(Tokyo) 47 Pages: 26-28
• [Journal Article] The galectin-3 gene promoter binding proteins in the liver of rats 48-h post-treatment with CCl4. (2006)
  • Author(s): Li F.
  • Journal Title: Gene 367 Pages: 46-55
• [Journal Article] Warning headache of subarachnoid hemorrhage and infarction due to vertebrobasilar artery dissection. (2006)
  • Author(s): Shibata T.
  • Journal Title: Clin. J. Pain. 22 Pages: 193-196
• [Journal Article] RAGE control of diabetic nephropathy in a mouse model : effects of RAGE gene disruption and administration of low molecular weight heparin. (2006)
  • Author(s): Myint K.M.
  • Journal Title: Diabetes 55 Pages: 2510-2522
• [Journal Article] Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice. (2006)
  • Author(s): Nomoto K.
  • Journal Title: J.Pathol. 210 Pages: 469-477
• [Journal Article] Preparation and observation of fresh-frozen sections of the green fluorescent protein transgenic mouse head. (2006)
  • Author(s): Tada M.
  • Journal Title: Acta Histochem. Cytochem. 39 Pages: 31-34
• [Journal Article] Neuroprotective role of transgenic PAF-acetylhydrolase II in mouse models of focal cerebral ischemia. (2006)
  • Author(s): Umemura K.
  • Journal Title: Stroke 38 Pages: 1063-1068
• [Journal Article] Transparent endoscopic sheath and rigid-rod endoscope used in endoscopic third ventriculostomy for hydrocephalus in the presence of deformed ventricular anatomy. (2006)
  • Author(s): Hayashi N.
  • Journal Title: J. Neurosurg 104 Pages: 321-325
• [Journal Article] Intracranial dural arteriovenous fistulas with retrograde cortical venous drainage : assessment with cerebral blood volume by dynamic susceptibility contrast magnetic resonance imaging. (2006)
  • Author(s): Noguchi K.
  • Journal Title: AJNR Am. J. Neuroradiol. 27 Pages: 1252-1256
• [Journal Article] Effect of arachnoid plasty using fibrin glue membrane after clipping of ruptured aneurysm on the occurrence of complications and outcome in the elderly patients. (2006)
  • Author(s): Mino Y.
  • Journal Title: Acta Neurochir.(Wien) 48 Pages: 627-631
• [Journal Article] Neuronal responses to a delayed-reward go/nogo task in the monkey posterior insular cortex. (2006)
  • Author(s): Asahi T.
  • Journal Title: Neuroscience 143 Pages: 627-639
• [Journal Article] Effect of arachnoid plasty using fibrin glue membrane after clipping of ruptured aneurysm on the occurrence of complications and outcome in the elderly patients. (2006)
  • Author(s): Mino Y.
  • Journal Title: Acta. Neurochir.(Wien) 148 Pages: 627-631
• [Journal Article] Enzymatic and biochemical properties of a novel human serine dehydratase isoform. (2006)
  • Author(s): Ogawa H.
  • Journal Title: Biochim. Biophys. Acta. 1764 Pages: 961-971
• [Journal Article] Verbal memory deficits in a preadolescent case of lesions of the left parahippocampal gyrus associated with a benign tumor. (2006)
  • Author(s): Sumiyoshi T.
  • Journal Title: Prog. Neuropsychopharmacol. Biol. Psychiaty. 30 Pages: 733-736
• [Journal Article] Characterization of diabetic nephropathy in CaM kinase IIalpha (Thr286Asp) transgenic mice.
  • Author(s): Suzuki H.
  • Journal Title: Biochem. Biophys. Res. Comm. (掲載確定)
  • Peer Reviewed
• [Presentation] CCl_4障害肝に誘導されるガレクチ-3の役割 (2008)
  • Author(s): 川口博、高畑正裕、張鴻、常山耕一、鄭華川、平賀紘一
  • Organizer: BMB2008(第31回日本分子生物学会年会、第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-11
• [Presentation] 肝機能維持に必要なガレクチンー3作用機序の解明. (2008)
  • Author(s): 川口 博
  • Organizer: 日本生化学会北陸支部第26回大会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-31
• [Presentation] 変異型CaM Kinase2(T286D)遺伝子導入マウスにおける重症糖尿病とその発症機序の解析. (2008)
  • Author(s): 加藤一郎
  • Organizer: MB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] CCl_4障害肝に誘導されるガレクチン- 3の役割. (2008)
  • Author(s): 川口 博
  • Organizer: MB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] Galectin-3 is required for the process of insulin excretion from pancreatic β-cells. (2008)
  • Author(s): Shehata M. H.
  • Organizer: MB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] Transgenic Mice overexpressing CaM KinaseII (T286D) in pancreatic beta cells have diabetic nephropathy with increased expression of PDGF-B chain. (2008)
  • Author(s): 鈴木ひかり
  • Organizer: MB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] インスリン分泌低下型糖尿病モデルマウスにおける糖尿病性腎症とPDGF経路についての検討. (2008)
  • Author(s): 鈴木ひかり
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 化学的障害肝で起こる情報伝達へのgalectin-3の果たす役割 (2007)
  • Author(s): 川口 博
  • Organizer: BMB2007(第30回日本分子生物学会年会・第80回日本生化学会大会合同大会)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] 家族性早期発症型認知症FENIBモデルマウスにおいて変異型ニューロセルピン(G397E)は小胞体とリソゾームに蓄積する (2007)
  • Author(s): 加藤一郎
  • Organizer: BMB2007(日本生化学会、日本分子生物学会合同年会)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] The mouse H-protein gene promoter is exonic (2007)
  • Author(s): Mohafez O.M.
  • Organizer: BMB2007(第30回日本分子生物学会年会・第80回日本生化学会大会合同大会)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] A putative role of two tandem open reading frames in exon l of the mouse H-protein gene (2007)
  • Author(s): Mohafez O.
  • Organizer: 日本生化学会北陸支部第25回大会
  • Place of Presentation: 金沢
  • Year and Date: 2007-05-26