2001 Fiscal Year Annual Research Report

球脊髄性筋萎縮症の神経細胞死の分子機構の解明

Research Project

Project/Area Number	12210010
Research Institution	Nagoya University
Principal Investigator	祖父江元名古屋大学, 大学院・医学研究科, 教授 (20148315)
Co-Investigator(Kenkyū-buntansha)	道勇学名古屋大学, 大学院・医学研究科, 教授 (90293703) 犬飼晃名古屋大学, 医学部・附属病院, 助手 (30314016)
Keywords	CAGリピート病 / ポリグルタミン鎖 / 神経細胞死 / 球脊髄性筋萎縮症 / アデノウイルスベクター / 培養神経系細胞モデル / DNA chip / 遺伝子発現解析
Research Abstract	CAGリピート病は・原因遺伝子のcoding region内にあるCAGリピートの異常延長により引き起こされる遺伝性神経変性疾患である.異常延長したCAGリピートがタンパクに翻訳されて異常延長ポリグルタミン鎖となり神経変性を起こすことが基本病態であると考えられているが,未だその分子メカニズムについては明らかではない.我々は今まで代表的CAGリピート病である球脊髄性筋萎縮症(SBMA)を中心にその病態発現機構について研究を行ってきた.今年度は強力なチキンベータアクチンプロモーターを用い異常延長ポリグルタミン鎖を持つヒト全長アンドロゲン受容体を強制発現させるトランスジェニックマウスを作製し,運動機能・病理学的検索を行うと共に,テストステロンを介した治療法の開発を行った.今回作製したトランスジェニックマウスはrota rodなどによる解析で雌に比し雄に強い運動機能障害を認め,生存期間も有意に雄で短縮を認めた.病理学的にも抗延長ポリグルタミン鎖特異抗体(1C2)で核が均一に染色されるdiffuse nuclear stainingを雄で有意に多く認めた.しかしながら神経細胞死および神経細胞脱落は明らかではなかった.テストステロンを介した治療法の開発では雄にcastrationを行うことで雌とほぼ同等にまで障害・生存期間の改善を認めた.一方雌にテストステロンを投与することで障害・生存期間の悪化を認めた.また雌に対するテストステロンの効果は用量依存性であった.今後はこのトランスジェニックマウスの病態発現機構を詳細に解析を行っていく.

Research Products

(10 results)

All Other

All Publications (10 results)

[Publications] Yoshihara T, et al.: "Differential expression of inflammation-and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis"Journal of Neurochemistry. 80. 158-167 (2002)
[Publications] Adachi H, et al.: "Transgenic mice with an expanded CAG repeat controlled by the human AR promotor show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death"Human Molecular Genetics. 10. 1039-1048 (2001)
[Publications] Doyu M, et al.: "Gene expression profile in Alzheimer's brain screened by molecular indexing"Molecular Brain Research. 87. 1-11 (2001)
[Publications] Niwa J, et al.: "A Novel Centrosomal RING-Finger Protein, Dorfin, Mediates Ubiquitin Ligase Activity"Biochemical and Biophysical Research Communications. 281. 706-713 (2001)
[Publications] Qiao S, et al.: "Differential Effects of Leukocyte Common Antigen-related Protein on Biochemical and Biological Activities of RET-MEN2A and RET-MEN2B Mutant Proteins"Journal of Biological Chemistry. 276. 9460-9467 (2001)
[Publications] Kobayashi Y, et al.: "Chaperones, Hsp7O and Hsp4O, suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract"Journal of Biological Chemistry. 275. 8772-8778 (2000)
[Publications] Ishigaki S, et al.: "Two Novel Genes, Human neugrin and Mouse m-neugrin, Are Upregulated with Neuronal Differentiation in Neuroblastoma Cells"Biochemical and Biophysical Research Communications. 279. 526-533 (2000)
[Publications] McCampbell A, et al.: "CREB-binding protein sequestration by expanded polyglutamine"Human Molecular Genetics. 9. 2197-2202 (2000)
[Publications] Watanabe H, et al.: "Differential somatic CAG repeat instability in variable brain cell lineage in dentrorubral pallidoluysian atrophy (DRPLA) : a laser-captured microdissection (LCM)-based analysis"Human Genetics. 107. 452-457 (2000)
[Publications] Sawada K, et al.: "Detection of Triplet Repeat Expansion in the Human Genome by Use of Hybridization Signal Intensity"Analytical Biochemistry. 286. 59-66 (2000)

2001 Fiscal Year Annual Research Report

球脊髄性筋萎縮症の神経細胞死の分子機構の解明

Principal Investigator

祖父江 元 名古屋大学, 大学院・医学研究科, 教授 (20148315)

Research Products

[Publications] Yoshihara T, et al.: "Differential expression of inflammation-and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis"Journal of Neurochemistry. 80. 158-167 (2002)

[Publications] Adachi H, et al.: "Transgenic mice with an expanded CAG repeat controlled by the human AR promotor show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death"Human Molecular Genetics. 10. 1039-1048 (2001)

[Publications] Doyu M, et al.: "Gene expression profile in Alzheimer's brain screened by molecular indexing"Molecular Brain Research. 87. 1-11 (2001)

[Publications] Niwa J, et al.: "A Novel Centrosomal RING-Finger Protein, Dorfin, Mediates Ubiquitin Ligase Activity"Biochemical and Biophysical Research Communications. 281. 706-713 (2001)

[Publications] Qiao S, et al.: "Differential Effects of Leukocyte Common Antigen-related Protein on Biochemical and Biological Activities of RET-MEN2A and RET-MEN2B Mutant Proteins"Journal of Biological Chemistry. 276. 9460-9467 (2001)

[Publications] Kobayashi Y, et al.: "Chaperones, Hsp7O and Hsp4O, suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract"Journal of Biological Chemistry. 275. 8772-8778 (2000)

[Publications] Ishigaki S, et al.: "Two Novel Genes, Human neugrin and Mouse m-neugrin, Are Upregulated with Neuronal Differentiation in Neuroblastoma Cells"Biochemical and Biophysical Research Communications. 279. 526-533 (2000)

[Publications] McCampbell A, et al.: "CREB-binding protein sequestration by expanded polyglutamine"Human Molecular Genetics. 9. 2197-2202 (2000)

[Publications] Watanabe H, et al.: "Differential somatic CAG repeat instability in variable brain cell lineage in dentrorubral pallidoluysian atrophy (DRPLA) : a laser-captured microdissection (LCM)-based analysis"Human Genetics. 107. 452-457 (2000)

[Publications] Sawada K, et al.: "Detection of Triplet Repeat Expansion in the Human Genome by Use of Hybridization Signal Intensity"Analytical Biochemistry. 286. 59-66 (2000)

祖父江元名古屋大学, 大学院・医学研究科, 教授 (20148315)