1996 Fiscal Year Annual Research Report

トリプレットリピート遺伝子変異による神経変性疾患の治療法の開発

Research Project

Project/Area Number	08407017
Research Institution	Niigata University
Principal Investigator	辻省次新潟大学, 脳研究所, 教授 (70150612)
Co-Investigator(Kenkyū-buntansha)	田中一新潟大学, 脳研究所, 助手 (20251845) 田中恵子新潟大学, 医学部附属病院, 助手 (30217020) 犬塚貴新潟大学, 医学部附属病院, 講師 (50184734)
Keywords	トリプレットリピート / トランスジェニックマウス / ポリグルタミン / アポトーシス / CAGリピート / 脊髄小脳変性症2型 / 歯状核赤核・淡蒼球ルイ体萎縮症
Research Abstract	トリプレットリピート病の発症機構を解明し,さらに治療法を開発することを目的に研究を行った。まず最初に,病的に伸長したトリプレットリピートを特異的に同定することにより,トリプレットリピート病の原因遺伝子を同定するために新たな原理を開発し,これを応用することにより,脊髄小脳変性症2型の原因遺伝子を単離することに成功し,その全構造を解明した。さらに,トリプレットリピートの伸長の程度と発症年齢との間に明瞭な負の相関関係があることを証明した。トリプレットリピート病における神経細胞変性機構を解明することを目的として,歯状核赤核・淡蒼球ルイ体萎縮症(dentatorubral-pallidoluysian atrophy,DRPLA)について次のような研究成果を得た。(1)培養細胞系については,アデノウイルスベクターを用いて全長の野生型および変異型DRPLA cDNAを高発現する実験系を世界に先駆けて確立した。このアデノウイルスベクターを用いて神経系の細胞にこれらの全長のcDNAの高発現を行い,神経細胞の変性機構を解析中である。(2)全長の変異からDRPLA cDNAをマウスに導入し,トランスジェニックマウスを作成し,中枢神経系において変異DRPLA cDNAを発現するトランスジェニックマウスの作成を完了した。現在,小脳失調の有無など表現系の観察を行っている。(3)全長の変異DRPLAゲノム遺伝子を単一コピーで有するマウスの作成を行い,マウスに導入されたヒト由来の変異DRPLA遺伝子のCAGリピートが不安定性を示すことを確認し,特にCAGリピートの不安定性に関与するゲノム上のcis-およびtrans-のエレメントについて現在詳細な解析を続行中である。

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] Ikeuchi,T.,et al.: "Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease : The mutant allele is preferentially transmitted in male meiosis." Am.J.Hum.Genet.58. 730-733 (1996)
[Publications] Takano,H.,et al.: "Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy : Cellular population-dependent dynamics of mitotic instability." Am.J.Hum.Genet.58. 1212-1222 (1996)
[Publications] Nakano,R.,et al.: "Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic lateral sclerosis." Neurosci.Lett.211. 129-131 (1996)
[Publications] Illarioshkin,S.N.,et al.: "X-linked nonproqressive congenital cerebellar hypoplasia : Clinical description and mapping to chromosome Xq." Ann.Neurol.40. 75-83 (1996)
[Publications] Ishikawa,A.,et al.: "Clinical analysis of 17 patients in 12 Japanese famillies with autosomal-recessive type juvenile parkinsonism." Neurology. 47. 160-166 (1996)
[Publications] Yoneda,M.,et al.: "Detection and quantification of point mutations in mitochondrial DNA by PCR." Methods in Enzymology. 264. 432-441 (1996)
[Publications] Shimizu,N.,et al.: "A sporadic case of dentatorubral pallidoluysian atrophy (DRPLA) with CAG repeat expansion but no clinical abnormalities in the father." J.Neurol.Neurosurg.Psychiat.61. 113-114 (1996)
[Publications] Igarashi,S.,et al.: "Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome : implications for the molecular mechanisms of the instability of the CAG repeat." Hum.Mol.Genet.5. 923-932 (1996)
[Publications] Okuizumi,K.,et al.: "Lack of association of very low density lipoprotein receptor gene polymorphism with Caucasian Alzheimer's disease." Ann.Neurol.40. 251-254 (1996)
[Publications] Sanpei,K.,et al.: "Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique,DIRECT." Nature Genet.14. 277-284 (1996)
[Publications] Tsuji,S.: "Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases." Jpn.J.Hum.Genet.41. 279-290 (1996)
[Publications] Onodera,O.,et al.: "Toxicity of expanded polyglutamine-domain proteins in escherichia coli." FEBS Lett.399. 135-139 (1996)
[Publications] Ikeuchi,T.,et al.: "Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9." Ann.Neurol.(in press).
[Publications] Matsumine,H.,et al.: "Localization of a gene for autosomal recessive form of juvenile parkinsonism (AR-JP) to chromosome 6g25.2-27." Am.J.Hum.Genet.(in press).
[Publications] Zhou,Y.X.,et al.: "Machado-Joseph disease in four Chinese pedigrees : Molecular analysis of 15 patients including 2 juvenile cases and clinical correlations." Neurology. (in press).

1996 Fiscal Year Annual Research Report

トリプレットリピート遺伝子変異による神経変性疾患の治療法の開発

Principal Investigator

辻 省次 新潟大学, 脳研究所, 教授 (70150612)

Research Products

[Publications] Ikeuchi,T.,et al.: "Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease : The mutant allele is preferentially transmitted in male meiosis." Am.J.Hum.Genet.58. 730-733 (1996)

[Publications] Takano,H.,et al.: "Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy : Cellular population-dependent dynamics of mitotic instability." Am.J.Hum.Genet.58. 1212-1222 (1996)

[Publications] Nakano,R.,et al.: "Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic lateral sclerosis." Neurosci.Lett.211. 129-131 (1996)

[Publications] Illarioshkin,S.N.,et al.: "X-linked nonproqressive congenital cerebellar hypoplasia : Clinical description and mapping to chromosome Xq." Ann.Neurol.40. 75-83 (1996)

[Publications] Ishikawa,A.,et al.: "Clinical analysis of 17 patients in 12 Japanese famillies with autosomal-recessive type juvenile parkinsonism." Neurology. 47. 160-166 (1996)

[Publications] Yoneda,M.,et al.: "Detection and quantification of point mutations in mitochondrial DNA by PCR." Methods in Enzymology. 264. 432-441 (1996)

[Publications] Shimizu,N.,et al.: "A sporadic case of dentatorubral pallidoluysian atrophy (DRPLA) with CAG repeat expansion but no clinical abnormalities in the father." J.Neurol.Neurosurg.Psychiat.61. 113-114 (1996)

[Publications] Igarashi,S.,et al.: "Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome : implications for the molecular mechanisms of the instability of the CAG repeat." Hum.Mol.Genet.5. 923-932 (1996)

[Publications] Okuizumi,K.,et al.: "Lack of association of very low density lipoprotein receptor gene polymorphism with Caucasian Alzheimer's disease." Ann.Neurol.40. 251-254 (1996)

[Publications] Sanpei,K.,et al.: "Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique,DIRECT." Nature Genet.14. 277-284 (1996)

[Publications] Tsuji,S.: "Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases." Jpn.J.Hum.Genet.41. 279-290 (1996)

[Publications] Onodera,O.,et al.: "Toxicity of expanded polyglutamine-domain proteins in escherichia coli." FEBS Lett.399. 135-139 (1996)

[Publications] Ikeuchi,T.,et al.: "Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9." Ann.Neurol.(in press).

[Publications] Matsumine,H.,et al.: "Localization of a gene for autosomal recessive form of juvenile parkinsonism (AR-JP) to chromosome 6g25.2-27." Am.J.Hum.Genet.(in press).

[Publications] Zhou,Y.X.,et al.: "Machado-Joseph disease in four Chinese pedigrees : Molecular analysis of 15 patients including 2 juvenile cases and clinical correlations." Neurology. (in press).

辻省次新潟大学, 脳研究所, 教授 (70150612)