2000 Fiscal Year Final Research Report Summary
Molecular Mechanisms for Purkinje Cell Degeneration and Demyelination in Prion Protein-Deficient Mice.
| Project/Area Number |
11694292
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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 |
Virology
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| Research Institution | Nagasaki University |
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Principal Investigator |
KATAMINE Shigeru Nagasaki University, Graduate School of Medical Sciences, Professor, 大学院・医学研究科, 教授 (40161062)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAGUCHI Suehiro Nagasaki University, Graduate School of Medical Sciences, Assistant Professor, 大学院・医学研究科, 講師 (60274635)
SHIGEMATSU Kazuto Nagasaki University, School of Medicine, Associate Professor, 医学部, 助教授 (20154205)
NIWA Masami Nagasaki University, School of Medicine, Professor, 医学部, 教授 (20136641)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Prion diseases / Prion protein / Neurodegeneration / RNA splicing / Gene-knockout mice |
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| Research Abstract |
Prion diseases, including Creutzfeldt-Jakob disease (CJD), are infectious neurodegenerative disorders. The etiological agent, prion, is postulated to consist mainly of a proteinase K-resistant isoform of prion protein (PrP^<Sc>) which is generated by post-translational conversion from the proteinase K-sensitive normal version (PrP^C) physiologically expressed on the surface of neuronal and glial cells. The constitutive conversion results in the tremendous accumulation of PrP^<Sc> in the prion-infected brain. Homozygous disruption of the Prnp gene encoding PrP^C renders mice resistant to prion, and the animals are no longer capable of generating PrP^<Sc>, indicating an essential role for PrP^<Sc> in the pathogenesis of prion diseases. The PrP-null mice (Ngsk Prnp^<0/0>) revealed progressive ataxia due to the degeneration of cellebellar Purkinje cells at old ages. Successful rescue of Ngsk Prnp^<0/0> mice from the neurodegeneration by a transgene encoding the normal mouse PrP^C has indicated that the functional loss of PrP^C is essential for this phenotype. Moreover, we detected aberrant mRNAs chimeric between Prnp exon 1-2 and a novel gene encoding PrP-like protein (PrPLP). These results suggested that, in addition to the functional loss of PrP^C, ectopic expression of the PrPLP in the brain of Ngsk Prnp^<0/0> mice could be associated with the Purkinje cell degeneration.
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