| Project/Area Number |
12670600
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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., FIRST DEPARTMENI OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (90221613)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Yoshitomo HAMAMATSU UNIV. SCH. OF MED., FIRST DEPARTMENI OF MEDICINE, RESEARCH ASSOCIATE, 医学部附属病院, 助手 (90303560)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | CERULOPLASMIN / MISSENSE MUTATION / IRON / LIPID PEROXIDATION / MITOCHONDRIA / FREE RADICAL / FERROXIDASE / SECRETORY PATHWAY / 銅 / 小胞体ストレス / 銅抱合能 / エネルギー産生系 / 遺伝子発現 / 小胞体 / タエロオキシダーゼ / フェロオキシダーゼ / 神経変性症 |
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| Research Abstract |
Aceruloplasminemia, an autosomal recessive disorder that affects iron metabolism, is caused by mutations of the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurologic disease. Almost all the mutations in the ceruloplasmin gene reported previously were truncation mutations. To elucidate the molecular pathogenesis of aceruloplasminemia, the ceruloplasmin biosynthesis of two missense mutants was examined. A P177R mutation results in the location of ceruloplasmin within the endoplasmic reticulum as apoprotein. An H978Q mutation results in detectable serum ceruloplasmin devoid of ferroxidase activity associated with decreased copper incorporation.
The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. We showed that an increased iron concentration is associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed cortical glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50% and 43% respectively for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62% and 65%. These findings suggest that iron-mediated free radicals may contribute to increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.
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