| Project/Area Number |
17300122
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Tokai University |
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Principal Investigator |
SUZUKI Kunihiko Tokai University, Future Science and Technology Joint Research Center, Professor, 未来科学技術共同研究センター, 教授 (30384895)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Junko Tokai University, Future Science and Technology Joint Research Center, Associate Professor, 未来科学技術共同研究センター, 助教授 (60363149)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2006: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2005: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Keywords | glycosphingolipid / sphingolipidosis / model mouse / neuropathology / ceramide / cerebellum / Purkinje cell |
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| Research Abstract |
The nervous system is rich in sphingolipids, and their physiological functions in the nervous system are drawing attention in a variety of cellular processes including differentiation, apoptosis and proliferation. Sphingolipidosis is the inherited diseases due to the abnormal metabolism of sphingolipids in lysosome. Most of the sphingolipidosis show the severe neurological dysfunction. Sphingolipid activator proteins (saposins A, B, C, D) are small homologous glycoproteins which are required for in vivo degradation of some sphingolipids. Previously we generated specific saposin A and D knockout mice that clarified their in vivo functions, saposin A as the essential activator of lysosomal galactosylceramidase (GALC) and saposin D as a lysosomal acid ceramidase activator. Saposin D knockout mice showed urinary system abnormalities and cerebellar Purkinje cell (PC) degeneration with accumulation of a-hydroxyl fatty acid-ceramide. We further investigated the neuropathological phenotype of
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saposin D^<-/-> mice and found the conspicuous pathological changes mainly in the cerebellum. In the cerebellum, cerebellar PC death progressed in a systematic pattern. The surviving PCs aligned symmetrically in stripes in coronal sections, that closely correspond to the expression pattern of Zebrin II and sphingosine kinase 1, possibly reflecting the neuroprotective effect of sphingosine 1-phosphate to the PCs of saposin D^<-/-> mice. Furthermore, the number of calbindin-immunoreactive cells was markedly decreased in the cerebral cortex, the amygdala and the hippocampal formation in the terminal stage. In the white matter of the cerebellum and spinal cord. perivascular clustering of periodic acid-Schiff (PAS)-positive macrophage-like cells were observed in paraffin embedded sections. These cells were prosaposin (precursor of mature saposins)-immunoreactive. These PAS-positive and prosaposin-immunoreactive inclusions were also observed conspicuously in the hippocampal CA3 pyramidal neurons. These results may provide an insight into the regional in vivo role of sphingolipids in the maintenance and function of the cerebellar PCs and the hippocampus. Less
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