1999 年度実績報告書

筋萎縮性側索硬化症の分子病態機序の解明

研究課題

研究課題/領域番号	10307015
研究機関	新潟大学
研究代表者	辻省次新潟大学, 脳研究所, 教授 (70150612)
研究分担者	中野亮一新潟大学, 医学部・附属病院, 助手 (00262444) 犬塚貴岐阜大学, 医学部, 教授 (50184734)
キーワード	筋萎縮性側索硬化症 / 運動ニューロン疾患 / コンフォメーション病 / Cu / Znスーパーオキシドディスムターゼ / SOD1 / 凝集体 / トランスジェニックマウス / 神経細胞変性
研究概要	本年度は,筋萎縮性側索硬化症(amyotrophic lateral sclerosis,ALS)の発症機序を明らかにし,さらに治療法開発のための基盤を作ることを目的として, 1.家族性ALS家系の詳細な遺伝子変異の解析, 2.アデノウイルスベクターによる発現系の構築, 3.変異Cu/Zn SOD遺伝子を導入したトランスジェニックマウスの作製を行った。Cu/Zn SOD遺伝子変異の解析については,家族性ALS33家系(37症例)について詳細な解析を行い,これまでに7家系で7種類のSOD1変異(Ala4Thr,lle104Phe,Leu106Val,lle111Phe,lle113Thr,Glu133Stop,Cys146Arg)を同定した。Ala4Thr変異,Cys111Tyr変異,Glu133Stop変異についてはこれまでに報告のない新しい変異であった。アデノウイルスベクターについては,野生型および変異Cu/Zn SOD遺伝子をアデノウイルスベクターに組み込み,培養細胞系でこれらのタンパクを高発現できる実験系の構築を行い,変異Cu/Zn SODが細胞質内凝集体を形成することを見いだした。変異Cu/Zn SOD遺伝子を導入したトランスジェニックマウスの作成については,Ala4Thr変異およびlle113Thr変異を対象としてトランスジェニックマウスの作成を行った。現在,lle113Thr変異マウスを3ライン得て,生後12ヶ月目より後肢に軽度の麻痺を生じるラインが得られている。本研究で得られた培養細胞系,トランスジェニックマウスの成果を基盤として,変異Cu/Zn SODタンバクによる細胞障害機構の解析をさらに進める予定である。

研究成果

(17件)

すべてその他

すべて文献書誌 (17件)

[文献書誌] Tomita, H., et al.: "Paroxysmal kinesigenic chorcoathetosis locus maps to chromosome 16p11.2-q12.1."Am.J. Hum. Genet.. (in press).
[文献書誌] Kokubo, Y., et al.: "Accumulation of neurofilaments and SOD1-immunoreactive products in a patient with familial amyotrophic lateral sclerosis with I113T SOD1 mutation."Arch. Neurol.. 56. 1506-1508 (1999)
[文献書誌] Sasaki, R., et al.: "Novel chloride channel gene mutations in two unrelated Japanese families awith Becker's autosomal recessive generalized myotonia."Neuromusc. Disord.. 9. 587-592 (1999)
[文献書誌] Ikeuchi, T., et al.: "A case of primary torsion dystonia in Japan with the 3-bp (CAG) deletion in the DYT1 gene with a unique clinical presentation."Neurogenetics. 2. 189-190 (1999)
[文献書誌] Ozawa, T., et al.: "Nocturnal decrease in vasopressin secretion into plasma in patients with multiple system atrophy."J. Neurol. Neurosurg. Psychiat.. 67. 542-545 (1999)
[文献書誌] Wakabayashi, K., et al.: "Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism."J. Neurol. Sci.. 165. 188-191 (1999)
[文献書誌] Matsuo, H., et al.: "Familial paroxysmal dystonic choreoathetosis. Clinical findings in a large Japanese family and genetic linkage to 2q."Arch. Neurol.. 56. 721-726 (1999)
[文献書誌] Sasaki, R., et al.: "A novel mutation in the gene for the adult skeletal muscle sodium channel α-subunit (CN4A) that causes paramyotonia congenita of von Eulenburg."Arch. Neurol.. 56. 692-696 (1999)
[文献書誌] Takano, H., et al.: "Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy (ALD)."Arch. Neurol.. 56. 295-300 (1999)
[文献書誌] Aoyagi, Y., et al.: "A de novo splice donor site mutation causes in-frame deletion of 14 amino acids in the proteolipid protein in Pelizaeus-Merzbacher disease."Ann. Neurol.. 46. 112-115 (1999)
[文献書誌] Ozawa, T., et al.: "No mutation in the entire coding region of the α-synucelin gene in pathologically confirmed cases of multiple system atrophy."Neurosci. Lett.. 270. 110-112 (1999)
[文献書誌] Wakamatsu, N., et al.: "Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism."J.Neurol. Neurosurg. Psychiat.. 67. 195-198 (1999)
[文献書誌] Hozumi, I., et al.: "Administration of prosaposin ameliorates spatial learning disturbance and reduces cavity formation following stab wounds in rat brain."Neurosci. Lett.. 267. 73-76 (1999)
[文献書誌] Toyooka, K., et al.: "14-3-3 protein ηchain gene (YWHAH) polymorphism and its genetic association with schizophrenia."Am. J. Med. Genet. (Neuropsychiat. Genet.). 88. 164-167 (1999)
[文献書誌] Ishikawa, A., et al.: "A non-familial Huntington's disease patient with grumose degeneration in the dentate nucleus."Acta Neurol. Scand.. 99. 322-326 (1999)
[文献書誌] Sato, T., et al.: "Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable to those in DRPLA patients."Hum. Mol. Genet.. 8. 99-106 (1999)
[文献書誌] Sato, A., et al.: "Adenovirus-mediated expression of mutant DRPLA proteins with expanded polyglutamine stretches in neuronally differentiated PC 12 cells. Preferential intranuclear aggregate formation and apoptosis."Hum. Mol. Genet.. 8. 997-1006 (1999)

1999 年度 実績報告書

筋萎縮性側索硬化症の分子病態機序の解明

研究代表者

辻 省次 新潟大学, 脳研究所, 教授 (70150612)

研究成果

[文献書誌] Tomita, H., et al.: "Paroxysmal kinesigenic chorcoathetosis locus maps to chromosome 16p11.2-q12.1."Am.J. Hum. Genet.. (in press).

[文献書誌] Kokubo, Y., et al.: "Accumulation of neurofilaments and SOD1-immunoreactive products in a patient with familial amyotrophic lateral sclerosis with I113T SOD1 mutation."Arch. Neurol.. 56. 1506-1508 (1999)

[文献書誌] Sasaki, R., et al.: "Novel chloride channel gene mutations in two unrelated Japanese families awith Becker's autosomal recessive generalized myotonia."Neuromusc. Disord.. 9. 587-592 (1999)

[文献書誌] Ikeuchi, T., et al.: "A case of primary torsion dystonia in Japan with the 3-bp (CAG) deletion in the DYT1 gene with a unique clinical presentation."Neurogenetics. 2. 189-190 (1999)

[文献書誌] Ozawa, T., et al.: "Nocturnal decrease in vasopressin secretion into plasma in patients with multiple system atrophy."J. Neurol. Neurosurg. Psychiat.. 67. 542-545 (1999)

[文献書誌] Wakabayashi, K., et al.: "Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism."J. Neurol. Sci.. 165. 188-191 (1999)

[文献書誌] Matsuo, H., et al.: "Familial paroxysmal dystonic choreoathetosis. Clinical findings in a large Japanese family and genetic linkage to 2q."Arch. Neurol.. 56. 721-726 (1999)

[文献書誌] Sasaki, R., et al.: "A novel mutation in the gene for the adult skeletal muscle sodium channel α-subunit (CN4A) that causes paramyotonia congenita of von Eulenburg."Arch. Neurol.. 56. 692-696 (1999)

[文献書誌] Takano, H., et al.: "Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy (ALD)."Arch. Neurol.. 56. 295-300 (1999)

[文献書誌] Aoyagi, Y., et al.: "A de novo splice donor site mutation causes in-frame deletion of 14 amino acids in the proteolipid protein in Pelizaeus-Merzbacher disease."Ann. Neurol.. 46. 112-115 (1999)

[文献書誌] Ozawa, T., et al.: "No mutation in the entire coding region of the α-synucelin gene in pathologically confirmed cases of multiple system atrophy."Neurosci. Lett.. 270. 110-112 (1999)

[文献書誌] Wakamatsu, N., et al.: "Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism."J.Neurol. Neurosurg. Psychiat.. 67. 195-198 (1999)

[文献書誌] Hozumi, I., et al.: "Administration of prosaposin ameliorates spatial learning disturbance and reduces cavity formation following stab wounds in rat brain."Neurosci. Lett.. 267. 73-76 (1999)

[文献書誌] Toyooka, K., et al.: "14-3-3 protein ηchain gene (YWHAH) polymorphism and its genetic association with schizophrenia."Am. J. Med. Genet. (Neuropsychiat. Genet.). 88. 164-167 (1999)

[文献書誌] Ishikawa, A., et al.: "A non-familial Huntington's disease patient with grumose degeneration in the dentate nucleus."Acta Neurol. Scand.. 99. 322-326 (1999)

[文献書誌] Sato, T., et al.: "Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable to those in DRPLA patients."Hum. Mol. Genet.. 8. 99-106 (1999)

[文献書誌] Sato, A., et al.: "Adenovirus-mediated expression of mutant DRPLA proteins with expanded polyglutamine stretches in neuronally differentiated PC 12 cells. Preferential intranuclear aggregate formation and apoptosis."Hum. Mol. Genet.. 8. 997-1006 (1999)

1999 年度実績報告書

辻省次新潟大学, 脳研究所, 教授 (70150612)