2005 Fiscal Year Final Research Report Summary
Molecular basis of aceruloplasminemia : Expression of the ceruloplasmin gene in aceruloplasminemia
| Project/Area Number |
15590885
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
MIYAJIMA Hiroaki Hamamatsu Univ Sch of Med, Dept of Medicine, Associated Professor, 医学部, 助教授 (90221613)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Yoshitomo Hamamatsu University Hospital, Dept of Medicine, Research associate, 医学部附属病院, 助手 (90303560)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Ceruloplasmin / Iron metabolism / Gene mutation / Loss-of-function / Endplasmic reticulum / Gene expression / Neuronal cell death / Ferroxidase |
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| Research Abstract |
Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. About 38 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.
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