2000 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
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)。

Research Products
(18 results)

All Other

All Publications (18 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)
[Publications] Osuga H, et al: "Cyclin-dependent kinases as a therapeutic target for stroke."Proc Natl Acad Sci. 97・18. 10254-10259 (2000)
[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)
[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)
[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)
[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)
[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)
[Publications] Kaneko S, et al: "Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function."Science. 289・5479. 633-637 (2000)
[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)
[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)
[Publications] Shimohata T, et al: "Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription."Nat Genet.. 1. 29-36 (2000)
[Publications] Ohara K, et al: "A CAG trinucleotide repeat expansion and familial schizophrenia."Psychiatry Res.. 94・3. 257-262 (2000)
[Publications] Kakizuka A: "Molecular Mechanisms underlying neuronal cell death in polyglutamine diseases."Neurochemical Research. 25. 990-991 (2000)
[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
[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
[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).
[Publications] Takeuchi N, et al: "Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6."Neurology. 54・4. 860-866
[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)

2000 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] 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)

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

[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)

[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)

[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)

[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)

[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)

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

[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)

[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)

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

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

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

[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

[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

[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).

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

[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)

池田穣衛東海大学, 総合医学研究所, 教授 (50266467)