1999 Fiscal Year Annual Research Report

筋萎縮性側索硬化症の分子病態機序の解明

Research Project

Project/Area Number	10307015
Research Institution	Niigata University
Principal Investigator	辻省次新潟大学, 脳研究所, 教授 (70150612)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	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
Research Abstract	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。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] Tomita, H., et al.: "Paroxysmal kinesigenic chorcoathetosis locus maps to chromosome 16p11.2-q12.1."Am.J. Hum. Genet.. (in press).
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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 Fiscal Year Annual Research Report

筋萎縮性側索硬化症の分子病態機序の解明

Principal Investigator

辻 省次 新潟大学, 脳研究所, 教授 (70150612)

Research Products

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

辻省次新潟大学, 脳研究所, 教授 (70150612)