Molecular mechanism of pathogenesis of Batten disease
| Project/Area Number |
04670168
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Juntendo University School of Medicine |
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Principal Investigator |
KOMINAMI Eiki Juntendo Univ., School Med., Professor, 医学部, 教授 (10035496)
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| Co-Investigator(Kenkyū-buntansha) |
EZAKI Junji Juntendo Univ., School Med., Assistant, 医学部, 助手 (60232948)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1992: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Subunit c / Mitochondria / ATP synthase / batten disease / Lysosomal storage / Delay of degradation / サブユニット蓄積症 / タンパク分解 / リソソーム |
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| Research Abstract |
The neuronal ceroid lipofuscinoses (NCL) are a goroup of recessively inherited neurogenerative disease of infants, children and young adults that lead to blindness, seizures, dementia and premature death. Palmer and coworkers recently demonstrated that in ovine NCL the major protein stored in identical to subunit c of the mitochondrial F_0F_1ATP synthase complex. We demonstrated immunochemically that a particularly high concentration of subunit c is specifically stored in lysosomes in the brains and in fibroblast cell lines from the late infantile cases of this disease. To explore the mechanism of storage of subunit c, the rates of degradation and synthesis of subunijt c were measured in fibroblasts cell lines from controls and patients with late infantile form. The radiolabel from subunit c decreased with time in control cells, whereas no apparent loss of radioactivity of subunit c was found in patient cells. There were no significant differences between control cells and cells with disease in the degradation of cytochrome c oxidase subunit IV, an inner membrane protein of mitochondria. A combination of pulse-chase and subcellular fractionation analysis showed that a delay of intramitochondrial loss from prelabeled subunit c was seen in all diseased cells tested. Lysosomal appearance of labeled subunit c could be detected after chase for more than 1 week. The biosynthetic rate of subunit c was almost the same in both control adn patient cells. Northern blotting analyzes showed that mRNAs for Pa and P2 genes had no significant difference in lengths and amounts between control and patient cells. Results suggest a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. This is the first direct evidence ot show a delay of subunit c degradation ion the cells from the late infantile form of Batten disease.
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Report
(3 results)
Research Products
(8 results)
