2001 Fiscal Year Final Research Report Summary
LYSOSOMAL PROTEIN STORAGE DISEASE
| Project/Area Number |
12470040
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
KOMINAMI Eiki Juntendo University, School of Medicine, Professor, 医学部, 教授 (10035496)
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| Co-Investigator(Kenkyū-buntansha) |
TANIDA Isei Juntendo University, School of Medicine, Assistant, 医学部, 助手 (30296868)
EZAKI Junji Juntendo University, School of Medicine, Assistant Professor, 医学部, 講師 (60232948)
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| Project Period (FY) |
2000 – 2001
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| Keywords | neuronal ceroid lipofuscinosis / Subunit c / ATP synthase / lysosome / tripeptidyl peptidase I / cathepsin / カテプシンD / ノックアウトマウス |
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| Research Abstract |
The neuronal ceroid lipofuscinoses (NCLs) are a closely related group of recessively inherited neurodegenerative diseases. Many types of NCL except for the infantile form are pathologically characterized by the massive lysosomal storage of subunit c of the mitochondrial ATP synthase complex in neurons and a wide variety of cells. In present studies the requirements for the lysosomal degradation of subunit c and relation of protein storage with neuropathological features were analysed. Following results are obtained 1) A lysosomal serine protease, tripeptidyl peptidase I (TPP-I) is directly involved in both the in vitro and in vivo degradation of subunit c, and a deficiency in TPP-I activity causes the lysosomal deposition of subunit c. 2) The further degradation of subunit c, after the initial cleavage by TPP-I, occurs rapidly, via the participation of cathepsin D and other lysosomal proteinases, and that cleavage by TPP-I constitutes the rate limiting step. 3) In fact cathepsin D-knockout mice showed a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis. Subunit c was found to accumulate in the lysosomes of neurons. 4) NO production via iNOS activity in microglia and peripheral macrophages in CD-/-mice contributes to secondary tissue damages such as neuropathological changes. 5) The developmental expression profiles of TPP-I and cathepsin D in rat brain showed that they continued to accumulate past the point of neuronal mass growth and in adult brains, indicating a requirement for either lysosomal or other functions in the adult brain.
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[Publications] Koike, M., H.Nakanishi, P.Saftig, J.Ezaki, K.Isahara, Y.Ohsawa, W.Schulz-Schaeffer, T.Watanabe, S.Waguri, S.Kametaka, M.ShibatamK.Yamamoto, E.Kominami, C.Peters, K.von Figura, and Y.Uchiyama.: "Cathepsin D deficiency induces lusosomal storage with ceroid lipofuscin in mouse CNS neurons."J Neurosci. 20. 6898-906 (2000)
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[Publications] Nakanishi, H., J.Zhang, M.Koike, T.Nishioku, Y.Okamoto, E.Kominami, K.von Figura, C.Peters, K.Yamamoto, P.Saftig, and Y.Uchiyama.: "Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice."J Neurosci. 21. 7526-33 (2001)
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