^Laboratory of Prion Diseases,Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818 Japan

Comparative analyses of three mouse-adapted scrapie strains G1, Obihiro, and 13/15 and

pathogenesis of G1 strain-induced polyuria in ICR mice

Motohiro Horiuchi^ Yu-koh Tamura^ and Hidefumi Furuoka^

^Laboratory of Prion Diseases,Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818 Japan

^Laboratory of Veterinary Public Health ^Laboratory of Veterinary Pa- thology, Obihiro University of Agriculture and Veterinary Medicine

<e-mail> horiuchi@vetmed.hokudai.ac.jp

Abstract

The causative agent of transmissible spongiform encephalopathies, prion, is thought to be composed mainly of abnormal isoform of prion protein (PrP^^). Although prion is devoid of agent-specific nucleic acid, there exist prion strains that are characterized biologically. Distribution of neuropathological lesions is one of the phenotyes of prion strains, how- ever, there are only a few reports that addressed the linkage of the clinical manifestations to neuropathological lesions. In this study, we compared the biological, biochemical, and neuropathological differences among three mouse adapted-scrapie strains, Gl, 13/15, and Obihiro. Gl exhib- ited longer incubation periods (—330 days) than others in mice carrying Pj.pA/A aHQ^pg Eighty percent of Gl strain-infected ICR mice showed severe obesity and polyuria. Diffuse deposition of PrP^^ was widespread in cerebral cortex, hippocampus of 13/15 and Obihiro strain-infected mice, while in Gl strain-infected mice, deposition of PrP^^ was rather restricted in the thalamus and hypothalamus and large PrP amyloid plaques were observed in cerebral cortex. PrP^^ of three strains could also be distin- guished in combination of relative proteinase K resistance and glycoform patterns. Serum concentration insulin and leptin levels were remarkable high in Gl-infected ICR mice with obesity, suggesting endocrinopathy and/or carbohydrate metabolism failure. PrP^^-deposition and neuronal vacuolation were observed the regions in hypothalamus including su- prachiasmatic nucleus, supraoptic nucleus and paraventricular nucleus.

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Kinetic analysis indicated that vasopressin-positive cells in these nuclei

decreased along with the progression of the neuronal degeneration. In

contrast, vasopressin-positive cells in these nuclei were detected even at

the terminal stage of Gl-infected C57BL/J6 mice that did not exhibit

polyuria. These results suggest that Gl-affected ICR mice developed

hypothalamic diabetes insipidus. The particular characteristics of Gl

strain would be useful for further analyzing the target cell specificity of

prion and pathogenesis of prion diseases.