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単一遺伝子異常による神経細胞死

Research Project

Project/Area Number 09280105
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionTokai University

Principal Investigator

池田 穣衛 (池田 穰衛)  東海大学, 総合医学研究所, 教授 (50266467)

Co-Investigator(Kenkyū-buntansha) 辻 省次  新潟大学, 脳研究所, 教授 (70150612)
永津 俊治  藤田保健衛生大学, 総合医科学研究所, 教授 (40064802)
金澤 一郎  東京大学, 大学院・医学研究科, 教授 (30110498)
佐々木 秀直  北海道大学, 大学院・医学研究科, 講師 (80281806)
垣塚 彰  大阪バイオサイエンス研究所, 第4研究部, 部長(研究職) (80204329)
黒沢 良和  藤田保健衛生大学, 総合医科学研究所, 教授 (10109259)
Project Period (FY) 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥240,000,000 (Direct Cost: ¥240,000,000)
Fiscal Year 2000: ¥60,000,000 (Direct Cost: ¥60,000,000)
Fiscal Year 1999: ¥56,000,000 (Direct Cost: ¥56,000,000)
Fiscal Year 1998: ¥60,000,000 (Direct Cost: ¥60,000,000)
Fiscal Year 1997: ¥64,000,000 (Direct Cost: ¥64,000,000)
Keywords神経細胞死 / ポリグルタミン病 / アポトーシス / NAIP / トリブレットリピートインスタビリティー / ハンチントン病 / MJD / DRPLA / ポリグルタミン酸 / トリプレットリピートインスタビリティー / ダイナミックミューテーション / 神経変性疾患 / トリプレットリピート病 / 小脳変性疾患 / 脊髄性筋萎縮症 / マシャドジュセフ病 / 分子医学 / 歯状核赤核淡蒼球ルイ体萎縮症
Research Abstract

各神経変性疾患の平成12年度の成果は以下のように要約される。
【脊髄性筋萎縮症】NAIPの細胞特異的な発現にかかわる調節因子を同定した。NAIPの抗アポトーシス活性は酸化ストレス(ONOO)に特異的で、活性化にはストレス特異的に誘導されるプロテアーゼによるプロセッシングが必要であることが明らかになった(池田)。【ハンチントン病】病変型CAGリピートを有するハンチントン病遺伝子exon1の核内凝集体を精製し、構成成分としてヒストンコアタンパク質、hnRNP/HFにユビキチンが含まれていることを明らかにした(金澤)。病変型HD遺伝子(77CAG)ノックインマウスは、小脳を除いた脳組織全体でCAGリピートが伸長化して、組織全体でモザイク化していた。この現象は、線条体等で早期から観察され、週齢依存的に伸長化した。老齢マウスでは核内封入体が観察される等、ヒトHD患者との高い類似性が観察された(永津)。In vitro系を用いてCAGリピートの伸長複製を試みたが、異常複製は極めて低い頻度で起こりCAG特異的な増幅複製を再現することはできなかった。(黒沢)。内因性病変型HDトランスジェニックミニブタF1固体、2系統(雄1、雌1;現在3ヶ月齢、)が得られた。死産、若年死亡した3系統のF1固体について解析中(池田)。【歯状核赤核淡蒼球ルイ体萎縮症】伸長ポリグルタミン鎖とTAF130(TATA-bindingprotein-associated factor)が結合すること、この結合がcAMP-reponsive element-binding protein(CREB)-依存性の転写活性を強く抑制することを見いだした(辻)。【マシャド・ジョセフ病】MJDタンパク質の伸長ポリグルタミン特異的に結合する因子polyglutamine interacting protein 1:PIP1を精製・同定した。この分子の変異体は発現培養細胞において空胞形成と細胞死を引き起こす(垣塚)。MJD蛋白質はポリグルタミンの伸長の有無に関わらず、ゴルジ装置に凝集(coiled-coil領域が関与)した場合に強い細胞障害を起こす(西澤)。【優性遺伝性脊髄小脳変性症】新規の優性遺伝性運動失調症(1家系)SCA14遺伝子座、19q13.4を決定した(佐々木)。

Report

(4 results)
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (76 results)

All Other

All Publications (76 results)

  • [Publications] Matsuyama N, et al: "Identification and characterization of the miniature pig Huntington's disease gene homolog : evidence for conservation and polymorphism in the CAG triplet repeat."Genomics. 69・1. 72-85 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Osuga H, et al: "Cyclin-dependent kinases as a therapeutic target for stroke."Proc Natl Acad Sci. 97・18. 10254-10259 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Saitoh Y, et al: "The RS447 human megasatellite tandem repetitive sequence encodes a novel deubiquitinating enzyme with a functional promoter."Genomics. 67・3. 291-300 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshizawa T, et al: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch."Hum Mol Genet. 9・1. 69-78 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Jeong SY, et al: "Identification of a novel human voltage-gated sodium channel alpha subunit gene, SCN12A."Biochem Biophys Res Commun.. 267・1. 262-270 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suzuki T, et al: "Molecular cloning of a novel apoptosis-related gene, human Nap1 (NCKAP1), and its possible relation to Alzheimer disease."Genomics.. 63・2. 246-254 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kubota T, et al: "Activation of autoreactive T cells that help nucleobindin-injected mice produce anti-DNA antibodies."Immunol Lett.. 75・2. 111-115 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kaneko S, et al: "Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function."Science. 289・5479. 633-637 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mogi M, et al: "Increase in level of tumor necrosis factor-alpha in 6-hydroxydopamine-lesioned striatum in rats is suppressed by immunosuppressant FK506."Neurosci Lett.. 289・3. 165-168 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamada M, et al: "Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches."Acta Neuropathol. 99・6. 615-618 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimohata T, et al: "Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription."Nat Genet.. 1. 29-36 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohara K, et al: "A CAG trinucleotide repeat expansion and familial schizophrenia."Psychiatry Res.. 94・3. 257-262 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kakizuka A: "Molecular Mechanisms underlying neuronal cell death in polyglutamine diseases."Neurochemical Research. 25. 990-991 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Maeda H, et al: "Rapid detection of candidate metastatic foci in the orthotopic inoculation model of androgen-sensitive prostate cancer cells introduced with green fluorescent protein."Prostate. 45. 335-340

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamashita I, et al: "A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter."Ann Neurol. 48・2. 156-163

    • Related Report
      2000 Annual Research Report
  • [Publications] Namekawa M, et al: "A large Japanese SPG4 famly with a novel inserton mutation of the SPG4 gene : aclinical and genetic study"J Neurol Sci. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Takeuchi N, et al: "Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6."Neurology. 54・4. 860-866

    • Related Report
      2000 Annual Research Report
  • [Publications] Sasaki H, et al: "Prevalence of triplet repeat expansion in ataxia patients from Hokkaido. the northernmost island of Japan."J Neurol Sci. 75・1. 45-51 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hadano, S. et al..: "A years artificia chromosome-based physical map of the juvenile amyottophic latest selerosis(ALS) entical region on human chroimosome 2q33-34"Genomics. 55. 106-112 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Marumoto, K. et al..: "Ovarian NAIP is an ooccyte survival factor during ovarian follicular development"Mol. Eprod. Dcv.. 54. 103-111 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamamoto, K. et al.: "Identification of two distincttranscipts for the neuronal apoptosis inhibitory proten(NAIP) gene"Biochem Biophys Res Commun. 264. 998-108 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hazeki N. et al.: "Ripid aggregate formation of the human N-terminal fragment carring an expanded polyglutamine tract"Biochem Biophys Res Commun. 256. 361-366 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Waragai M. et al.: "QBP-1, a novelpolyglutamine tract-bunding protein, inhibitst rransceipuon acuvation by Bm-2 and affects cdll survival"Human Molecular Genetics. 8. 977-987 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] C. Miyazaki. et al.: "Changes in the specificity of antibodies by site-specific mutagenesis followed by random mutagensis"Prigeun Engineer. 12. 107-415 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K, Hashimoto. et al.: "Conservation and diversification of MHC class I and its related molecules inverebrate"Immonol. Rev.. 167. 81-100 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ichinose, H. et al.: "Nikrecykar cloning of the human Nur1 gene - Characterization of the human gene and cDNAs"Gene. 230. 233-239 (0999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mogi, M. et al.: "Increase in level of tumor necrosis factor(TNF)-a in 6-hydroxydopamine-lesioned striaturn in rats without influence of systemic L-DOPA on the TNF-a induction"Neurosi, Lett. 268. 99-106 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sato T. et al.: "Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-depndent intergenerational and somatic insrtabilities of CAG repeats comparable to those in DRPLA patients"Hum. Mol. Genet. 8. 99-106 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sato A. et al.: "Adenovirus-mediated in neuronally differentiated PC12 cells. Preferential intrauclear aggregate formation and apoptosis"Hum. Mol. Genet. 8. 997-1006 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Koide R. et al.: "Aneurological disease caused by an expanded CAG tranucleotide repeat in the TATA-binding protein gene : a new polyglutamine disease?"Hum. Mol. Genet. 268. 2047-2053 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sanchez, I. et al.: "Caspase-8 is required for cell death induced by expanded polyglitamine repeats"Neuron. 22. 623-633 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yasuda, S. et al.: "Triggering of neuronal cell death by accumuration of activated SEKI on nuclea polygutamine aggregation in PML bodies"Genes to Cells. 4. 743-756 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takimiya T. et al.: "Single sperm analysis of the CAG repeats in the gene fordentatorubal-pallidoluysian atophy(DRPLA) : the instablity of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases"Hum Mol Genet. 8. 453-457 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawakami T. et al.: "A case of McLeod syndrome with unusually severe myopathy"J Neurol Sci. 246. 841-845 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsura T. et al.: "Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type2(SCA2)"J Neurol. 246. 835-839 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Pang J. et al.: "A commondisease haplotype in spinocerebellar ataxia 2(SCA2) pedigress of diverse ethnic origin"Eur Hum Genet. 7. 841-845 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hadano S,et al: "The primary structure and genomic organaization of five novel transcripts located close to the Huntington's disease gene on human chromosome 4p16.3." DNA Research. 5. 177-186 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chen.Q,et al: "Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy genes SMN and NAIP." Genomics. 48. 121-127 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Song.J,et al: "Genomic organization and expression of a human gene for Myc-associated zinc finger pritein(MAZ)" J Biol Chem. 273. 20603-20614 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kobayashi.K,et al: "An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy" Nature. 394. 388-392 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yasui.Y,et al: "Temperature dependency of the thermodynamic parameters in interactions between hen egg-white lysozyme(HEL)and anti-HEL antibody." J.Biochem. 123. 827-831 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kubota.T,et al: "Upregulation of nucleobindin expression in human-activated lymphocytes and non-Hodgkins lymphoma." Pathology International. 48. 22-28 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ishiguro.H,et al: "Identification and charac terization of a novel phorbol ester-responsive DNA sequence in the 5ユ flanking region of the human dopamine b-hydroxylase gene." Journal of Biological Chemistry. 273. 21942-21949 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Cubells.J.F.,et al: "Dopamine b-hydroxylase:two polymorphisms in linkage disequilibrium at the structural gene DBH-associate with biochemical phenotypic variation." Human Genetics. 102. 533-540 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Igarashi.S,et al: "Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch." Nature Genet. 18. 111-117 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ikeuchi.T,et al: "A novel long and unstable CAG/CTG trinucleotide repeat on chromosome 17q." Genomics. 49. 321-326 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Wellington.C.L.,et al: "Caspase Cleavage of gene products a ssocated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract." Journal of Biological Chemistry. 273. 9158-9167 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamaguchi.M,et al: "Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells." Proceeding of National Academy of Science U.S.A. 95. 7491-7496 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takiyama.Y,et al: "Maternal anticipation in Machado-Joseph disease(MJD):some familial factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family." J Neurol Sci. 155. 141-145 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fan D-S,et al: "Prevention of dopaminergic neuron death by adeno-associated virus vector-mediated GDNF gene transfer in rat mesencephalic cells in virto." Neurosci Lett. 243. 61-64 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sasaki.H,et al: "Neuropathological and molecular studies of spinocerebellar ataxia type 6(SCA6)." Acta Neuropathol. 95. 141-145 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ikeuchi.T,et al: "A novel long and unstable CAG/CTG trinucleotide repeat on chromosome 17q." Gemomics. 49. 321-326 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Saitoh.Y: "Chromosome microdissection and microcloning" Chromosome Research. 5. 77-80 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kogi.M: "A novel tamdem repeat sequence location on human chromosome 4p:Isolation and characterization" Genomics. 42. 278-283 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Xu.D.G.: "Elavation of neuronal expression of NAIP redces ischemic damage in the rat hippocampus." Nature Medicine. 3. 997-1004 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ichikawa.Y: "A Japanese family carrying a novel mutation in the Emery-Dreifuss muscular dystrophy gene." Ann.Neurol.41. 339-402 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yazawa.I: "Expression of dentatorubral-pallidoluysian atrophy(DRPLA)proteins in patients." Neuroscience Letters. 255. 53-56 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Wang.G: "Machado-Joseph disease gene product identified in lymphocytes and brain." Biochemical and Biophysical Research Communicarions. 233. 476-479 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Seimiya: "Identification of POU-class homeobox genes in freshwater sponge and the specific expression of these genes during differentiation." Eur.J.Biochem.243. 27-31 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Akahori: "Nucleotide sequences of all the gamma gene loci of murine immunoglobulin heavy chains." Genomics. 41. 100-104 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Iba: "Expression vectors for introduction of highly diverged sequences into the six complementarity-determining regions of antibody." Gene. 194. 35-46 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nagatsu.T: "GTP cyclohydrolase I gene,dystonia,juvenile parkinsonism,and Parkinson's disease." J.Neural Transm.Supplement 49. 203-209 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Higashiyama.S: "A novel brain-derived member of the epidormal growth factor family that interacts with Erb B3 and Erb B4." J.Biochem.122. 675-680 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kobayashi.K: "Controled genetic ablatron by immunotoxin mediated cell targeting." In:Houdebine,L.M.(Ed.),Transgenic Animals:Generation and Use,Harwood Academic Publishers,Amsterdam,. 331-336 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Oyake.M: "Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy(DRPLA)cDNA:Strong conservation of a polymorphic CAG repeat in the murine gene." Genomics. 40. 205-507 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsumine.H: "Localization of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2-27." Am.J.Hum.Genet.60. 588-596 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ikeuchi.T: "Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome9." Ann.Neuro.41. 432-437 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hasumoto.K: "Association of expression of mRNA encoding the PGF2a receptor with luteal cell apoptosis in ovaries of pseudopregnant mice." J.Repro.Fertil.109. 45-52 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suzuki.F: "Cloning,functional expression and tissue distribution of rabbit a 1 d-adrenoc eptor." Biochim.Biophys.Acta. 12323. 6-11 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe.N: "p140mDia,a mammalian homolog of Dorosophila diaphanous,is a target protein for Rho small GTPas and is a ligand for profilin." EMBO J.16. 3044-3056 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takiyama.Y: "Machado-Joseph disease:cerebellar ataxia and autonomic dys-function in a patient with the shortest known expanded allele(56 CAG repeat units)of the MJD1 gene." Neurology. 49. 604-606 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ishikawa.K: "Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1." Am.J.Hum.Genet.61. 336-346 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Liu X.-Z.: "Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene." Nature Genet. 17(in press). (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fukazawa.T: "Dominantly inherited leukodystrophy showing cerebellar deficits and spastic paraparesis:a new entity?" J.Neurol.244. 446-449 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sasaki.H: "Neuropathological and molecular studies of spinocerebellar ataxia type 6(SCA6)." Acta Neuropathologica. (in press). (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsuura.T: "Autosomal dominant spastic paraplegia:clinical and genetic studies of a large Japanese pedigree linked to chromosome 2p." J.Neurol.Sci.(in press). (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2017-10-11  

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