1999 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) 清水信義慶応義塾大学, 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	昨年度原因遺伝子のポジショナルクローニングに成功した常染色体性劣性遺伝の家族性パーキンソン病の原因遺伝子(parkin)につき、変異解析及び遺伝子産物の機能解析を推進した。国内外から集積した200以上のサンプルについて変異解析を行い、家系により種類の異なる変異を多数発見した。多くは欠失変異であるが点突然変異の家系も存在することが判明した。一方臨床症候は一致していても、抹消血DNAのPCRにて変異が検出できない家系が相当数あることも判明し、これらの多くは異なる変異をそれぞれの相同染色体に持つcompound heterozygotes であるとの予測をたて、これを検出する方法を確立した。この方法により色々な種類のcompound heterozygotes がみつかりつつある。更にparkin 蛋白の機能解析を推進、本蛋白が細胞質及びGolgi 体にあり、軸索輸送を受ける蛋白であることを明らかにし、更にubiquitin ligase の一種である可能性を示した。弧発型パーキンソン病の発症機構に関しては、遺伝子危険因子、酸化的ストレス、アポトーシス、内因性黒質神経毒に関する研究を推進し、内因性に生じるサルソリノールの一種が、強力な黒質毒性を有し、アポトーシスを誘導することを明らかにした。またパーキンソン病の黒質で核酸の酸化的障害で生じる8-HO-dGTPase及び8-HO-deoxyguanine が細胞質において上昇していることを論文に発表した。更に、パーキンソン病の遺伝子治療についての研究を推進し、ラットモデルへの遺伝子導入に成功し、現在サルについての研究を行い、ヒトの遺伝子治療をめざした研究を行っている。

Research Products

(38 results)

All Other

All Publications (38 results)

[Publications] Mizuno Y: "Genetics of Parkinson's disease"Biomed Pharmacother. 53. 109-116 (1999)
[Publications] Shimura H: "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autocomal Juvenile Parkinsonism pationts"Ann Neurol. 45. 668-672 (1999)
[Publications] Wang M.: "Polymorphism in the Parkin gene in sporadic Parkinson's disease"Ann Neurol. 45. 655-658 (1999)
[Publications] Shimura-Miura H,: "Increased 8-oxo=dGTPase in the mitochondria of substantia nigra neurons in Parkinson's disease Ann Neurol 46: 920-924. 1999"Ann Neurol. 46. 920-924 (1999)
[Publications] Kitada T: "Positional cloning of the autosomal recessive juvenile parkinsonism (AR-JP) gene and its diversity in deletion mutations"Parkinsonism Rel Disord. 5. 163-168 (1999)
[Publications] Oya T: "Mehtylglyoxal modification of protein"J Biol Chem. 274. 18492-18502 (1999)
[Publications] Sumitomo M: "Induction of apoptosis on cytokine-producing bladder cancer cells by adenovirus-mediated over expression"Hum Gene Ther. 10. 37-47 (1999)
[Publications] Heino M: "Mutation analyses of north American APS-1 patients"Hum Mutat. 13. 69-74 (1999)
[Publications] Minoshima S: "Keio Mutation Database for Eye Disease Genes (KMeyeDB)"Nuc Acids Res. 27. 358-361 (1999)
[Publications] Shimura-Miura H,: "Increased 8-oxo=dGTPase in the mitochondria of substantia nigra neurons in Parkinson's disease. Ann Neurol 46: 920-924, 1999"Ann Neurol. 46. 920-924 (1999)
[Publications] Mashima Y: "A novel mutation at codon 124(R124L) in the BIGH3 gene is associated with a superficial variant of granular corneal dystrophy"Arch Ophthalmol. 117. 91-93 (1999)
[Publications] *hang X: "Identification and mutation analysis of DOC-1R, a DOC-1 growth suppressor-related gene"Biochem Biophys Res Commun. 255. 59-63 (1999)
[Publications] Yamakawa T: "Biosynthesis of a parkinsonism-preventing substrance, 1-methyl-1, 2, 3, 4-tetrahydroiso-quinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondria"Neurosci Let. 259. 157-160 (1999)
[Publications] Kawai H: "Dopaminergic activity of endogenous 1BnTIQ derivatives"Neurochem Res. 24. 127-127 (1999)
[Publications] T. Yamakawa: "Biosynthesis of 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline, an endogenous parkinsonism-preventing substance in the brain"Neurochem Res. 24. 129-129 (1999)
[Publications] Maruyama W: "An endogenous MPTP-like dopaminergic neurotoxin, N-methyl(R)salsolinol, in the cerebrospinal fluid decreases with progression of Parkinson's diease"Neurosci Lett. 262. 13-16 (1999)
[Publications] Akao Y: "Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3"Neurosci Left. 267. 153-156 (1999)
[Publications] Naoi M: "Cell death of dopamine neurons in aging and Parkinson's disease"Mechan Ageing Develop. (in press). (1999)
[Publications] Borgeld H-JW: "Appropriately spaced nuclear localizing signals are necessary for efficient nuclear impor of non-nuclear proteins"Biochem Biophys Res Commun. 256. 278-283 (1999)
[Publications] Iwata-Ichikawa E: "Glial cells protect neuronal cells against oxidative stress via transcriptional up-regulatior of the glutathione system"J Neurochem. 72. 2334-2344 (1999)
[Publications] Kondo Y: "Immunohistochemical localization of connective tissue growth factor in the rat central nervous system"Brain Res. 834. 146-151 (1999)
[Publications] Iida M: "Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist"Brain Res. (in press).
[Publications] Kawahara N: "The gene for heparin-binding epidermal growth factor-like growth factor is stress-inducible: its role in cerebral ischemia"J Cereb Blood Flow Metab. 19. 307-320 (1999)
[Publications] *e T: "Ubiquitin stress response in postischemic hippocampal neurons under nontolerant and tolerant conditions"J Cereb Blood Flow Metab. 19. 750-756 (1999)
[Publications] Ogasawara Y: "Efficient production of adeno-associated virus vectors using split type helper plasmids"Jpn J Cancer Res. 90. 476-483 (1999)
[Publications] Ikemoto K: "Cholonergic neurons with monoamine oxidase type B (MAOB)-activity in the laterodorsal tegmental nucleus of mouse"Neurosci Lett. 271. 53-56 (1999)
[Publications] Ikemoto K: "Tyrsine hydroxylase and aromatic L-amino acid decarboxylase do not coexist in neurons in the human anterior cingulate cortex"Neurosci Lett. 269. 37-40 (1999)
[Publications] Onozuka M: "Reduced mastication stimulates impairment of spatial memory and degeneration of hippocampal neurons in aged SAMP8 mice"Brain Res. 826. 148-153 (1999)
[Publications] Nagatsu I: "Specific localization of the guanosine triphosphate (GTP) cyclehydrolase l-immunoreactivity in the human brain"J Neural Transm. (in press).
[Publications] Karasawa N: "Age-associated changes in the dopamine synthesis as determined by GTP cycle hydrolase l inhibitor in the brain of senescence-accelerated mouse-prone inbred strains"J Neurosci Res. (in press).
[Publications] Yagita Y: "Molecular cloning of a novel member of the HSP110 family of genes, ischemia-responsive protein 94kDa (irp94), expressed in rat brain after transient forebrain ischemia"J Neurochem. 72. 1544-1551 (1999)
[Publications] Ueda H: "A combined analysis of regional energy metabolism and immunohistochemical ischemic damage in the gerbil brain"J. Neurochem. 72. 1232-1242 (1999)
[Publications] Yagita Y: "DNA cleavage and proteolysis of microtubule-associated protain 2 after cerebral ishemia of different severity"Neuroscience. 92. 1417-1424 (1999)
[Publications] Kitagawa K: "Species differences in fodrin proteolysis in the ischemic brain"J Neurosci Res.. 55. 643-649 (1999)
[Publications] Ozawa K: "Strategies for gene therapy of Parkinson's disease using adeno-associate d virus (AAV) vectors"Biogenic Amines. 15. 21-37 (1999)
[Publications] *rabe M.: "Charged-to-alanine scanning mutagenesis of the N-terminal half of adeno-associated virus type 2 Rep78 protein"J Virol. 73. 2682-2693 (1999)
[Publications] Mizuno Y: "Genetic spects in Parkinson's disease. In: Mental Dysfunction in Parkinson's Disease II"Academic Pharmaceutical Productions. 53 (1999)
[Publications] Shimizu N: "Current Status, Keio Strategy and Prospects In: Mental Dysfunction in Parkinson's Disease II"Springer-Verlag Tokyo. 5 (1999)

1999 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] Mizuno Y: "Genetics of Parkinson's disease"Biomed Pharmacother. 53. 109-116 (1999)

[Publications] Shimura H: "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autocomal Juvenile Parkinsonism pationts"Ann Neurol. 45. 668-672 (1999)

[Publications] Wang M.: "Polymorphism in the Parkin gene in sporadic Parkinson's disease"Ann Neurol. 45. 655-658 (1999)

[Publications] Shimura-Miura H,: "Increased 8-oxo=dGTPase in the mitochondria of substantia nigra neurons in Parkinson's disease Ann Neurol 46: 920-924. 1999"Ann Neurol. 46. 920-924 (1999)

[Publications] Kitada T: "Positional cloning of the autosomal recessive juvenile parkinsonism (AR-JP) gene and its diversity in deletion mutations"Parkinsonism Rel Disord. 5. 163-168 (1999)

[Publications] Oya T: "Mehtylglyoxal modification of protein"J Biol Chem. 274. 18492-18502 (1999)

[Publications] Sumitomo M: "Induction of apoptosis on cytokine-producing bladder cancer cells by adenovirus-mediated over expression"Hum Gene Ther. 10. 37-47 (1999)

[Publications] Heino M: "Mutation analyses of north American APS-1 patients"Hum Mutat. 13. 69-74 (1999)

[Publications] Minoshima S: "Keio Mutation Database for Eye Disease Genes (KMeyeDB)"Nuc Acids Res. 27. 358-361 (1999)

[Publications] Shimura-Miura H,: "Increased 8-oxo=dGTPase in the mitochondria of substantia nigra neurons in Parkinson's disease. Ann Neurol 46: 920-924, 1999"Ann Neurol. 46. 920-924 (1999)

[Publications] Mashima Y: "A novel mutation at codon 124(R124L) in the BIGH3 gene is associated with a superficial variant of granular corneal dystrophy"Arch Ophthalmol. 117. 91-93 (1999)

[Publications] *hang X: "Identification and mutation analysis of DOC-1R, a DOC-1 growth suppressor-related gene"Biochem Biophys Res Commun. 255. 59-63 (1999)

[Publications] Yamakawa T: "Biosynthesis of a parkinsonism-preventing substrance, 1-methyl-1, 2, 3, 4-tetrahydroiso-quinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondria"Neurosci Let. 259. 157-160 (1999)

[Publications] Kawai H: "Dopaminergic activity of endogenous 1BnTIQ derivatives"Neurochem Res. 24. 127-127 (1999)

[Publications] T. Yamakawa: "Biosynthesis of 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline, an endogenous parkinsonism-preventing substance in the brain"Neurochem Res. 24. 129-129 (1999)

[Publications] Maruyama W: "An endogenous MPTP-like dopaminergic neurotoxin, N-methyl(R)salsolinol, in the cerebrospinal fluid decreases with progression of Parkinson's diease"Neurosci Lett. 262. 13-16 (1999)

[Publications] Akao Y: "Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3"Neurosci Left. 267. 153-156 (1999)

[Publications] Naoi M: "Cell death of dopamine neurons in aging and Parkinson's disease"Mechan Ageing Develop. (in press). (1999)

[Publications] Borgeld H-JW: "Appropriately spaced nuclear localizing signals are necessary for efficient nuclear impor of non-nuclear proteins"Biochem Biophys Res Commun. 256. 278-283 (1999)

[Publications] Iwata-Ichikawa E: "Glial cells protect neuronal cells against oxidative stress via transcriptional up-regulatior of the glutathione system"J Neurochem. 72. 2334-2344 (1999)

[Publications] Kondo Y: "Immunohistochemical localization of connective tissue growth factor in the rat central nervous system"Brain Res. 834. 146-151 (1999)

[Publications] Iida M: "Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist"Brain Res. (in press).

[Publications] Kawahara N: "The gene for heparin-binding epidermal growth factor-like growth factor is stress-inducible: its role in cerebral ischemia"J Cereb Blood Flow Metab. 19. 307-320 (1999)

[Publications] *e T: "Ubiquitin stress response in postischemic hippocampal neurons under nontolerant and tolerant conditions"J Cereb Blood Flow Metab. 19. 750-756 (1999)

[Publications] Ogasawara Y: "Efficient production of adeno-associated virus vectors using split type helper plasmids"Jpn J Cancer Res. 90. 476-483 (1999)

[Publications] Ikemoto K: "Cholonergic neurons with monoamine oxidase type B (MAOB)-activity in the laterodorsal tegmental nucleus of mouse"Neurosci Lett. 271. 53-56 (1999)

[Publications] Ikemoto K: "Tyrsine hydroxylase and aromatic L-amino acid decarboxylase do not coexist in neurons in the human anterior cingulate cortex"Neurosci Lett. 269. 37-40 (1999)

[Publications] Onozuka M: "Reduced mastication stimulates impairment of spatial memory and degeneration of hippocampal neurons in aged SAMP8 mice"Brain Res. 826. 148-153 (1999)

[Publications] Nagatsu I: "Specific localization of the guanosine triphosphate (GTP) cyclehydrolase l-immunoreactivity in the human brain"J Neural Transm. (in press).

[Publications] Karasawa N: "Age-associated changes in the dopamine synthesis as determined by GTP cycle hydrolase l inhibitor in the brain of senescence-accelerated mouse-prone inbred strains"J Neurosci Res. (in press).

[Publications] Yagita Y: "Molecular cloning of a novel member of the HSP110 family of genes, ischemia-responsive protein 94kDa (irp94), expressed in rat brain after transient forebrain ischemia"J Neurochem. 72. 1544-1551 (1999)

[Publications] Ueda H: "A combined analysis of regional energy metabolism and immunohistochemical ischemic damage in the gerbil brain"J. Neurochem. 72. 1232-1242 (1999)

[Publications] Yagita Y: "DNA cleavage and proteolysis of microtubule-associated protain 2 after cerebral ishemia of different severity"Neuroscience. 92. 1417-1424 (1999)

[Publications] Kitagawa K: "Species differences in fodrin proteolysis in the ischemic brain"J Neurosci Res.. 55. 643-649 (1999)

[Publications] Ozawa K: "Strategies for gene therapy of Parkinson's disease using adeno-associate d virus (AAV) vectors"Biogenic Amines. 15. 21-37 (1999)

[Publications] *rabe M.: "Charged-to-alanine scanning mutagenesis of the N-terminal half of adeno-associated virus type 2 Rep78 protein"J Virol. 73. 2682-2693 (1999)

[Publications] Mizuno Y: "Genetic spects in Parkinson's disease. In: Mental Dysfunction in Parkinson's Disease II"Academic Pharmaceutical Productions. 53 (1999)

[Publications] Shimizu N: "Current Status, Keio Strategy and Prospects In: Mental Dysfunction in Parkinson's Disease II"Springer-Verlag Tokyo. 5 (1999)

水野美邦順天堂大学, 医学部, 教授 (30049043)