2000 Fiscal Year Final Research Report Summary
Pathophysiology of spinocerebellar degeneration /retinitis pigmentosa linked to a point mutation of alpha-tocopherol transfer protein gene
Project/Area Number |
10557064
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Research Category |
Grant-in-Aid for Scientific Research (B).
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Allocation Type | Single-year Grants |
Section | 展開研究 |
Research Field |
Neurology
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Research Institution | Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience (1999-2000) Tokyo Metropolitan Institute for Neuroscience (1998) |
Principal Investigator |
UCHIHARA Toshiki Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 研究員 (10223570)
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Co-Investigator(Kenkyū-buntansha) |
YOKOTA Takanori Tokyo Medical and Dental University, Faculty of Medicine, Lecturer, 医学部, 講師 (90231688)
INOUE Keizo University of Tokyo, Faculty of Pharmaceutics, Professor, 薬学部, 教授 (30072937)
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Project Period (FY) |
1998 – 2000
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Keywords | alpha-tocopherol transfer protein / vitamin E deficiency / knock out / hereditary ataxias |
Research Abstract |
The first autopsy case with progressive ataxia and retinitis pigmentosa associated with a mutation of the gene coding for alpha-tocopherol transfer protein (aTTP) was investigated. In addition to retinal lesion and dying-back type degeneration in the posterior column of the spinal cord, comparable to those reported in cases or animal model with deficiency of vitamin E, mild degeneration was noted in the cerebellar cortex. Mouse model with deleted aTTP was generated, where massive accumulation of lipofuscin was noted in the anterior horn cells of the spinal cord in addition to posterior column lesion. Because these spinal lesions were exaggerated or attenuated by excess intake or deficiency of vitaminE, respectively, effects of deleted a TTP gene is mediated by lowered vitaminE concentration in the tissue. On the other hand, vitaminE concentration in the cerebellum of the autopsy case mentioned above is normalized except for the cerebellum after long term administration of vitamin E.If the metabolic pathway of vitamin E in the cerebellum is different, a mutation of aTTP gene may have affected it and lead to cerebellar degeneration. Because similar cerebellar lesion was not detectable in model mice with deleted a TTP gene, molecular pathway involving aTTP and its regional difference should be further investigated. Hereditary ataxias of other origins were also investigated with special attention to neuronal intranuclear inclusions (NIIs). Immunolocalization of ataxin-2, -3 was investigated in a series of autopsy brains including various CAG repeat disorders and neuronal intranuclear hyaline inclusion disease (NIHID). It was found that the presence of ataxin-2 or -3 in the NIIs was not specific for SCA2 or SCA3, respectively. We invented dual intensification technique for double-labeled immunofluorescence, which is now proved to be very effective for immunohistochemistry applicable to a wide range of disorders including vitamineE and aTTP abnormality.
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Research Products
(21 results)
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[Publications] Yokota, T., Uchihara T., Kumagai, J., Shiojiri, T., Pang, JJ., Arita, M., Arai, H., Hayashi, M., Kiyosawa, M., Okeda, R., Mizusawa, H.: "A postmortem study of ataxia with retinitis pigmentosa by mutation of α-tocopherol transfer protein gene."J Neurol Neurosurg Psychiat. 68 (4). 521-525 (2000)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Ishida, K., Mitoma, H., Song, SY., Uchihara, T., Inaba, A., Eguchi, S., Kobayashi, T., Mizusawa, H.: "Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase."Annals of Neurol.. 46 (2). 62-67 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Koyano, S., Uchihara, T., Fujigasaki, H., Nakamura, A., Yagishita, S., Iwabuchi, K.: "Neuronal intranuclear inclusions in spinocerebellar ataxia type 3 : triple-labeling immunofluorescent study."Neurosci Lett. 273 (2). 117-120 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Yaginuma, M., Ishida, K., Uchihara, T., Suzuki, F., Aoki, M., Tanaka, T., Nurase, H., Ikeda, K., Mizusawa, H.: "Paraneoplastic cerebellar ataxia with mild cerebello-olivary degeneration and an anti-neuronal antibody : a clinicopathological study."Neuropathol Appl Neurobio. 26 (6). 568-572 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Koyano, S., Uchihara, T., Fujigasaki, H., Nakamura, A., Yagishita, S., Iwabuchi, K.: "Neuronal intranuclear inclusions in spinocerebellar ataxia type 2 (Letter)"Ann Neurol. 47 (4). 550 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Takahashi, J., Fukuda, T., Tanaka, J., Minamitani, M., Fujigasaki, H., Uchihara, T.: "Neur onal intranuclear hyaline inclusion disease wityh polyglutamine-immunoreactive inclusions."Ann Neuro. 47 (4). 550 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Toru, S., Murakoshi, T., Ishikawa, K., Saegusa, H., Fujigasaki, H., Uchihara, T., nagaya ma, S., Osanai, M.Mizusawa, H., Tanabe, T.: "Spinocerebella ataxia type 6 mutation alters P-type calcium channel function."J.Biol Chem 275 (15). J Biol Chem (15). 10893-10898 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Fujigasaki, H., Uchihara, T., Koyano, S., Iwabuchi, K., Yagishita, S., Makifuchi, T.Nakamura, A., Ishida, K., Toru. S.Hirai, S Ishikawa, K., Tanabe, T., Mizusawa H.: "Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains."Exp Neurol. 165 (2). 248-256 (2000)
Description
「研究成果報告書概要(欧文)」より