Comparative analyses of three mouse-adapted scrapie strains G1, Obihiro, and I3/I5 and pathogenesis of G1 strain-induced polyuria in ICR mice

Abstract

The causative agent of transmissible spongiform encephalopathies, prion, is thought to be composed mainly of abnormal isoform of prion protein (PrP^Sc). 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, however, 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, G1, I3/I5, and Obihiro. G1 exhibited longer incubation periods (∼330 days) than others in mice carrying PrP^A/A allotype. Eighty percent of G1 strain-infected ICR mice showed severe obesity and polyuria. Diffuse deposition of PrP^Sc was widespread in cerebral cortex, hippocampus of I3/I5 and Obihiro strain-infected mice, while in G1 strain-infected mice, deposition of PrP^Sc was rather restricted in the thalamus and hypothalamus and large PrP amyloid plaques were observed in cerebral cortex. PrP^Sc of three strains could also be distinguished in combination of relative proteinase K resistance and glycoform patterns. Serum concentration insulin and leptin levels were remarkable high in G1-infected ICR mice with obesity, suggesting endocrinopathy and/or carbohydrate metabolism failure. PrP^Sc-deposition and neuronal vacuolation were observed the regions in hypothalamus including suprachiasmatic nucleus, supraoptic nucleus and paraventricular nucleus. 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 G1-infected C57BL/J6 mice that did not exhibit polyuria. These results suggest that G1-affected ICR mice developed hypothalamic diabetes insipidus. The particular characteristics of G1 strain would be useful for further analyzing the target cell specificity of prion and pathogenesis of prion diseases.