1999 Fiscal Year Annual Research Report

単一遺伝子異常による神経細胞死

Research Project

Project/Area Number	09280105
Research Institution	Tokai University
Principal Investigator	池田穣衛東海大学, 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・医学系研究科, 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)
Keywords	神経細胞死 / ポリグルタミン酸 / アポトーシス / NAIP / トリプ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
Research Abstract	平成11年度の特筆すべき成果は、(1)CAGリピート溝の特徴である伸長ポリグルタミン鎖を有する異常タンパクは核内凝集体を形成しそれに伴って核構造変化なぴに核機能障害さらに細胞死を誘起することが示された、(2)ハンチントン病様病兆を呈するHDトランスジェニックミニブタ個体が得られた、(3)脊髄性筋萎縮責任遺伝子産物(NA1P〉の癸現調節領域が同定され、NAlPは限定された細胞死(ラジカル)を阻止する明らかになった、等である。各神経変性疾の原因遺伝子産物の機能解析における研究成果の概要脊髄性筋萎籍症【NAIPの発現調節に関わるcis-elementの全構造と細胞特異的発現調節因子(タンパク)を同定した。NA1Pは限定された細胞死を阻止し、かつ特異的なプロセシングが明らかになった(池田)ハンチントン病】ハンチンチンのエクソン1のみで形成される核内凝集体にヒストン3が含まれていることを見出した(金澤)。ノックイン(77CAG)ハンチントン病モデルマウスは生後20週令から脳特異的(特に線条体)にCAGリピートの不安定性を示すことが明かになった(永津)。HDトランスジェニツクミニブタのうち、生後4ヶ月から錐体街路系異常による旋回運動を呈する個体(雄)が得られた(池田)。CAGリピートDNA複製過程に特異的な複製型DNA構造を識別できる抗体ライブラリーの作製に成功した(黒澤)。【歯状核赤核淡蒼球ルイ体萎縮症】伸長ポリグルタミン鎖による細胞障害機構は、伸長ポリグルタミン鎖を有する変異タンパクの核内凝集体の形成に伴う核の機能障書による可能性を見いだした(辻)。【マシャド・ジョセフ病】ポリグルタミンは、核内のPMLbodyに凝集体を作り、SEK1-JNK細胞死kinaseカスケードが活性化されることを見いだした(垣塚)。ポリQ近傍のN末に核への移行シグナル、C末には核からの排出シグナルを確認した。さらにC末端はγ-tubulinとも相互作用して、microtubulus organizing centerに凝集体を形成させることが明らかになった(西澤)。【優性遺伝性脊髄小脳変性症】遺伝子異常が未同定であった優性遺伝性脊髄小脳変性症1家系について、その原因遺伝子のマッピングに成功した(佐々木)。

Research Products
(18 results)

All Other

All Publications (18 results)

[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)
[Publications] Marumoto, K. et al..: "Ovarian NAIP is an ooccyte survival factor during ovarian follicular development"Mol. Eprod. Dcv.. 54. 103-111 (1999)
[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)
[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)
[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)
[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)
[Publications] K, Hashimoto. et al.: "Conservation and diversification of MHC class I and its related molecules inverebrate"Immonol. Rev.. 167. 81-100 (1999)
[Publications] Ichinose, H. et al.: "Nikrecykar cloning of the human Nur1 gene - Characterization of the human gene and cDNAs"Gene. 230. 233-239 (0999)
[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)
[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)
[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)
[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)
[Publications] Sanchez, I. et al.: "Caspase-8 is required for cell death induced by expanded polyglitamine repeats"Neuron. 22. 623-633 (1999)
[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)
[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)
[Publications] Kawakami T. et al.: "A case of McLeod syndrome with unusually severe myopathy"J Neurol Sci. 246. 841-845 (1999)
[Publications] Matsura T. et al.: "Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type2(SCA2)"J Neurol. 246. 835-839 (1999)
[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)

1999 Fiscal Year Annual Research Report

単一遺伝子異常による神経細胞死

Principal Investigator

池田 穣衛 東海大学, 総合医学研究所, 教授 (50266467)

Research Products

[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)

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

[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)

[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)

[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)

[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)

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

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

[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)

[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)

[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)

[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)

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

[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)

[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)

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

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

[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)

池田穣衛東海大学, 総合医学研究所, 教授 (50266467)