2000 Fiscal Year Annual Research Report

遺伝的素因と環境因子の相互作用による神経細胞死

Research Project

Project/Area Number	09280103
Research Institution	Juntendo University
Principal Investigator	水野美邦順天堂大学, 医学部, 教授 (30049043)
Co-Investigator(Kenkyū-buntansha)	直井信応用生化学研究所, 脳科学研究部門, 部長 (50022786) 太田茂広島大学, 医学部, 教授 (60160503) 清水信義慶應大学, 医学部, 教授 (50162706) 小澤敬也自治医科大学, 医学部, 教授 (30137707) 小川紀雄岡山大学, 医学部, 教授 (90033208)
Keywords	神経細胞死 / パーキンソン病 / 家族性パーキンソン病 / 遺伝的素因 / 黒質神経毒 / 環境因子 / 遺伝子治療 / 神経栄耀因子
Research Abstract	常染色体性劣性遺伝の家族性パーキンソン病の原因蛋白であるParkinについて機能解析を推進し,これがユビキチンリガーゼの一種であることを明らかにした.Parkinの欠損により,これによりポリユビキチン化される蛋白が黒質に蓄積して黒質変性が進行すると推定できる.またParkinは,Golgi装置を経て軸索輸送小胞に結合し,シナプス小胞に運ばれ,その膜に存在することを明らかにした.今後alpha-synucleinとの関連や孤発型パーキンソン病におけるParkinの解析で,パーキンソン病の原因に関する研究の進展が期待できる.Parkin遺伝子については,その欠失変異の切断点が18タイプに分類されることを明らかにした.エキソン4欠失の切断点は日本人5家系,韓国人1家系に共通していた.更にFISHプローブを調製し,複合ヘテロ接合体の欠失変異のDNA診断を可能にした. 孤発型パーキンソン病に関しては,PD患者リンパ球で内在性神経毒N-methyl(R)-salsolinol生成律速酵素である中性N-methyltransferase活性が著しく高い例が存在することを明らかにした.本神経毒はアポトーシスを誘導して黒質神経細胞死を起こす.更にpropargylamine誘導体はこの細胞死機構に介入しアポトーシスを抑制して神経細胞保護活性を示すことを見い出した.またドパミン系作用薬が核内移行し,転写因子に直接作用している可能性を明らかにした.パーキンソン病の遺伝子治療に関しては,チロシン水酸化酵素,芳香族アミノ酸脱炭酸酵素,テトラヒドロビオプテリン合成の律速酵素GTPシクロヒドロラーゼIの各遺伝子を全て搭載したアデノ随伴ウイルスベクターをMPTP投与により作製したラットモデルで1年以上改善が継続することを明らかにし,サルを用いた前臨床研究でも効果を確認した.

Research Products
(29 results)

All Other

All Publications (29 results)

[Publications] Shimura H, et al.: "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase"Nature Genet. 25. 302-305 (2000)
[Publications] Kobayashi T, et al.: "Exonic deletion mutations of the Parkin gene among sporadic patients with Parkinson's disease"Parkinsonism Rel Disord. 6. 129-131 (2000)
[Publications] Zhang J, et al.: "Polymeropoulos, M.H., Mizuno, Y. : Association between a polymorphism of ubiquitin carboxy-terminal hydrolase L1 gene and sparadic Parkinson's disease"Parkinsonism Rel Disord. 6. 195-197 (2000)
[Publications] Zhang J, et al.: "Failure to find mutations in ubiquitin caroboxy-terminal hydrolase L1 gene in familial Parkinson's disease"Parkinsonism Rel Disord. 6. 199-200 (2000)
[Publications] Hattori N, et al.: "Autosomal recessive juvenile parkinsonism : a Key to understanding nigral degeneration in sporadic Parkinson's disease"Neuropathology. 20. S85-S90 (2000)
[Publications] Kitada T, et al.: "Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene"Mammalian Genome. 11. 417-421 (2000)
[Publications] Minoshima S, et al.: "Keio Mutation Database (KMDB) for Human Disease Gene Mutations"Nucl Acids Res. 28. 364-368 (2000)
[Publications] Kuriyama H, et al.: "Characterization and Chromosomal Mapping of a Novel Human Gene, ANKHZN,"Gene. 253. 151-160 (2000)
[Publications] Ohtsubo M, et al.: "Interruption of NFkB-STAT1 Signaling Mediate EGF-induced Cell Cycle Arrest"J Cell Physiol. 184. 131-137 (2000)
[Publications] Sango, et al.: "Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain"Neurosci Lett. 283. 224-226 (2000)
[Publications] Maruyama W, et al.: "Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl (R) salsolinol, in dopaminergic SH-SY5Y cells."J.Neural Transm. (in press). (2000)
[Publications] Maruyama W, et al.: "Mechanism underlying anti-apoptotic activity of (-) deprenyl-related propargylamines"Mech Aging Devel. (in press). (2000)
[Publications] Sogawa CA, et al.: "Antioxidants protect against dopamine-induced metallothionein-III (GIF) mRNA expression in mouse glial cell line (VR-2g)"Brain Res. 853. 310-316 (2000)
[Publications] Higashi Y, et al.: "Inhibition of tyrosinase reduces cell viability in catecholaminergic neuronal cel"J Neurochem. 75. 1771-1774 (2000)
[Publications] Miyazaki I, et al.: "Expression of metallothionein-III mRNA and its regulation by Levodopa in the basal ganglia of hemi-parkinsonian rats"Neurosci Lett. 293. 65-68 (2000)
[Publications] Hayashi H, et al.: "Morphological aspects of the postnatal development of submandibular glands in malerats : Involvement of apoptosis"Neurosci Lett. 283. 224-226 (2000)
[Publications] Ikemoto K, et al.: "Human midbrain dopamine neurons express serotonin 2A receptor : an immunohistochemical demonstration"Brain Res. 853. 377-380 (2000)
[Publications] Kitahama K, et al.: "Distribution of dopamine-immunoreactive fibers in the rat brainstem"Neuroanatomy. 18. 1-9 (2000)
[Publications] Shen Y, et al.: "Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic I-amino acid decarboxylase, and GTP cyclohydrolase I"Gene Ther. 11. 1509-1519 (2000)
[Publications] Shimazaki K, et al.: "Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo : prospects for gene therapy of ischemia-induced neuronal death"Gene Ther. 7. 1244-1249 (2000)
[Publications] Urabe M, et al.: "Self amplification system for recombinant adeno-associated virus production"Biochem Biophys Res Commun. 276. 559-563 (2000)
[Publications] Tanaka M, et al.: "Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain"Mech Ageing Dev. 116. 65-76 (2000)
[Publications] Shimokata H, et al.: "Distribution of geriatric disease-related genotypes in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA)."Epidemiol. 10. S46-S55 (2000)
[Publications] Matsunaga H, et al.: "Anti-atherogenic mitochondrial genotype in patients with type 2 diabetes"Diabetes Care. (in press). (2000)
[Publications] Mabuchi T, et al.: "Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats"Stroke. 31. 1735-1743 (2000)
[Publications] Yang G, et al.: "Regional difference of neuronal vulnerability in the murine hippocampus after transient forebrain ischemia"Brain Res. 870. 195-198 (2000)
[Publications] Kitagawa K, et al.: "Extended neuronal protection induced after sublethal ischemia adjacent to the area with delayed neuronal death"Neuroscience. 96. 141-146 (2000)
[Publications] Asai A,T, et al.: "Hlgh level calcineurin activity predisposes neuronal cells to apoptosis"J Biol Chem. 274. 34450-34458 (2000)
[Publications] Kawai H, et al.: "Inhibition of dopamine receptors by endogenous amines : binding to striatal receptors and pharmacological effects on locomotor activity"Bioorg Medic Chem Lett. (in press). (2000)

2000 Fiscal Year Annual Research Report

遺伝的素因と環境因子の相互作用による神経細胞死

Principal Investigator

水野 美邦 順天堂大学, 医学部, 教授 (30049043)

Research Products

[Publications] Shimura H, et al.: "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase"Nature Genet. 25. 302-305 (2000)

[Publications] Kobayashi T, et al.: "Exonic deletion mutations of the Parkin gene among sporadic patients with Parkinson's disease"Parkinsonism Rel Disord. 6. 129-131 (2000)

[Publications] Zhang J, et al.: "Polymeropoulos, M.H., Mizuno, Y. : Association between a polymorphism of ubiquitin carboxy-terminal hydrolase L1 gene and sparadic Parkinson's disease"Parkinsonism Rel Disord. 6. 195-197 (2000)

[Publications] Zhang J, et al.: "Failure to find mutations in ubiquitin caroboxy-terminal hydrolase L1 gene in familial Parkinson's disease"Parkinsonism Rel Disord. 6. 199-200 (2000)

[Publications] Hattori N, et al.: "Autosomal recessive juvenile parkinsonism : a Key to understanding nigral degeneration in sporadic Parkinson's disease"Neuropathology. 20. S85-S90 (2000)

[Publications] Kitada T, et al.: "Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene"Mammalian Genome. 11. 417-421 (2000)

[Publications] Minoshima S, et al.: "Keio Mutation Database (KMDB) for Human Disease Gene Mutations"Nucl Acids Res. 28. 364-368 (2000)

[Publications] Kuriyama H, et al.: "Characterization and Chromosomal Mapping of a Novel Human Gene, ANKHZN,"Gene. 253. 151-160 (2000)

[Publications] Ohtsubo M, et al.: "Interruption of NFkB-STAT1 Signaling Mediate EGF-induced Cell Cycle Arrest"J Cell Physiol. 184. 131-137 (2000)

[Publications] Sango, et al.: "Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain"Neurosci Lett. 283. 224-226 (2000)

[Publications] Maruyama W, et al.: "Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl (R) salsolinol, in dopaminergic SH-SY5Y cells."J.Neural Transm. (in press). (2000)

[Publications] Maruyama W, et al.: "Mechanism underlying anti-apoptotic activity of (-) deprenyl-related propargylamines"Mech Aging Devel. (in press). (2000)

[Publications] Sogawa CA, et al.: "Antioxidants protect against dopamine-induced metallothionein-III (GIF) mRNA expression in mouse glial cell line (VR-2g)"Brain Res. 853. 310-316 (2000)

[Publications] Higashi Y, et al.: "Inhibition of tyrosinase reduces cell viability in catecholaminergic neuronal cel"J Neurochem. 75. 1771-1774 (2000)

[Publications] Miyazaki I, et al.: "Expression of metallothionein-III mRNA and its regulation by Levodopa in the basal ganglia of hemi-parkinsonian rats"Neurosci Lett. 293. 65-68 (2000)

[Publications] Hayashi H, et al.: "Morphological aspects of the postnatal development of submandibular glands in malerats : Involvement of apoptosis"Neurosci Lett. 283. 224-226 (2000)

[Publications] Ikemoto K, et al.: "Human midbrain dopamine neurons express serotonin 2A receptor : an immunohistochemical demonstration"Brain Res. 853. 377-380 (2000)

[Publications] Kitahama K, et al.: "Distribution of dopamine-immunoreactive fibers in the rat brainstem"Neuroanatomy. 18. 1-9 (2000)

[Publications] Shen Y, et al.: "Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic I-amino acid decarboxylase, and GTP cyclohydrolase I"Gene Ther. 11. 1509-1519 (2000)

[Publications] Shimazaki K, et al.: "Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo : prospects for gene therapy of ischemia-induced neuronal death"Gene Ther. 7. 1244-1249 (2000)

[Publications] Urabe M, et al.: "Self amplification system for recombinant adeno-associated virus production"Biochem Biophys Res Commun. 276. 559-563 (2000)

[Publications] Tanaka M, et al.: "Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain"Mech Ageing Dev. 116. 65-76 (2000)

[Publications] Shimokata H, et al.: "Distribution of geriatric disease-related genotypes in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA)."Epidemiol. 10. S46-S55 (2000)

[Publications] Matsunaga H, et al.: "Anti-atherogenic mitochondrial genotype in patients with type 2 diabetes"Diabetes Care. (in press). (2000)

[Publications] Mabuchi T, et al.: "Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats"Stroke. 31. 1735-1743 (2000)

[Publications] Yang G, et al.: "Regional difference of neuronal vulnerability in the murine hippocampus after transient forebrain ischemia"Brain Res. 870. 195-198 (2000)

[Publications] Kitagawa K, et al.: "Extended neuronal protection induced after sublethal ischemia adjacent to the area with delayed neuronal death"Neuroscience. 96. 141-146 (2000)

[Publications] Asai A,T, et al.: "Hlgh level calcineurin activity predisposes neuronal cells to apoptosis"J Biol Chem. 274. 34450-34458 (2000)

[Publications] Kawai H, et al.: "Inhibition of dopamine receptors by endogenous amines : binding to striatal receptors and pharmacological effects on locomotor activity"Bioorg Medic Chem Lett. (in press). (2000)

水野美邦順天堂大学, 医学部, 教授 (30049043)