| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2003: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥6,900,000 (Direct Cost: ¥6,900,000)
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| Research Abstract |
Certain lines of mice devoid of prion protein (PrP), such as Ngsk Prnp^<0/0>, exhibit late-onset ataxia due to Purkinje cell degeneration, which is rescued by a transgene encoding PrP. In these mice, PrP-like protein, PrPLP/Dpl, is ectopically expressed by neurons including Purkinje cells and glial cells. To explore mechanisms of the neurodegeneration, two types of transgenic (tg) mice expressing PrPLP/Dpl in all neurons, tg(N-PrPLPIDpI), or only Purkinje cells, tg(P-PrPLP/Dpl), were generated and subsequently backcrossed with non-ataxic Zrch I Prnp^<0/0> mice to eliminate the Prnp alleles. In contrast to the tg mice with the Prnp^<+/+> background, never showing neurological abnormalities, not only tg(N-PrPLP/Dpl) but also, tg(P-PrPLP/Dpl) mice with the Prnp^<0/0> alleles developed Purkinje cell degeneration after incubation periods inversely correlated to the expression levels of PrPLP/Dpl. Moreover, some of the tg mice hemizygous for Prnp allele (Prnp^<0+>) also succumbed to the dise
… More
ase but much later than those carrying the Prnp^<0/0> alleles. These results indicated that PrPLP/Dpl ectopically expressed by Purkinje cells itself executes a does-dependent deleterious effect on the cells, and that a stoichiometric antagonistic interaction between PrP and PrPLP/Dpl is crucially involved in the neurodegeneration. We next introduced five types of PrP transgenes including heterologous hamster and two mouse/hamster chimeric genes as well as two mutants, each of which encoded PrP lacking residues 23-88 (MHM2.del23-88) or with E199K substitution (Mo.E199K), into Ngsk Prnp^<0/0> mice. Only MHM2.de123-88 failed to rescue from the Purkinje cell death. Little difference was observed in pathology and onset of ataxia between Ngsk Prnp^<0/0> and MHM2.de123-88/Ngsk Prnp^<0/0>. No detergent-insoluble PrPLP/Dpl was detectable in the CNS of Ngsk Prnp^<0/0> even after the onset of ataxia. Our findings provide evidence that the N-terminal residues 23-88 of PrP containing the unique octapeptide-repeat region is crucial for preventing Purkinje cell death in the Prnp^<0/0> mice expressing PrPLP/Dpl in the neuron. Less
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