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Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein.

ABSTRACT: We analyzed the relationship between pathogenic protein expression and perturbations to brain anatomy and physiology in a genetic model of prion disease. In this model, the mouse line 1D4, neuropathology is promoted by accumulation of a cytosolic form of the prion protein (cyPrP). CyPrP distribution was determined and compared with anatomical magnetic resonance imaging (MRI) data, a form of functional MRI based on manganese labeling, and immediate early gene mapping with an antibody to c-Fos. Significant discrepancies between 1D4 and control mice became apparent well in advance of overt behavioral pathology in the mutant mice. Alterations to brain structure and function in the mutants varied among brain regions, however, and differed strikingly even among regions with the highest levels of cyPrP expression. In the cerebellum, gross neurodegeneration was accompanied by increased Mn(2+)-enhanced MRI signal, raising the possibility that compensatory mechanisms act to preserve cerebellar function in the face of massive atrophy. In the hippocampus of 1D4 mice, no significant structural alterations were observed, but both Mn(2+)-enhanced MRI and c-Fos data indicated perturbations to neurophysiology. In the neocortex, there were no clear neural activity differences between 1D4 and control animals, but mutant mice showed significant reduction in cortical thickness. Our finding that distinct combinations of anatomical and functional abnormalities accompanied cyPrP overexpression in different parts of the brain indicates the importance of context in conditioning effects of protein pathogens, and exemplifies the notion that neurodegenerative phenotypes extend beyond cell death and the immediate consequences of atrophy for particular neural systems.

SUBMITTER: Faas H

PROVIDER: S-EPMC7605312 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein.

Faas Henryk H Jackson Walker S WS Borkowski Andrew W AW Wang Xinhe X Ma Jiyan J Lindquist Susan S Jasanoff Alan A

NeuroImage 20091014 3

We analyzed the relationship between pathogenic protein expression and perturbations to brain anatomy and physiology in a genetic model of prion disease. In this model, the mouse line 1D4, neuropathology is promoted by accumulation of a cytosolic form of the prion protein (cyPrP). CyPrP distribution was determined and compared with anatomical magnetic resonance imaging (MRI) data, a form of functional MRI based on manganese labeling, and immediate early gene mapping with an antibody to c-Fos. Si ...[more]

PMID: 19835963

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Project description:Transgenic (Tg) mice expressing chimeras of mouse and human prion proteins (PrPs) have shorter incubation periods for Creutzfeldt-Jakob disease (CJD) prions than mice expressing full-length human PrP. Increasing the sequence similarity of the chimeric PrP to mouse PrP, by reverting human residues to mouse, resulted in a Tg line, denoted Tg22372, which was susceptible to sporadic (s) CJD prions in approximately 110 days.Mice expressing chimeric mouse/human PrP transgenes were produced. The mice were inoculated intracerebrally with extracts prepared from the brains of patients who died of CJD. Onset of neurological dysfunction marked the end of the incubation time. After sacrifice of the Tg mice, their brains were analyzed for PrP(Sc) and neuropathological changes.Reversion of 1 additional residue (M111V) resulted in a new Tg line, termed Tg1014, susceptible to sCJD prions in approximately 75 days. Tg1014 mice also have shorter incubation periods for variant (v) CJD prions, providing a more tractable model for studying this prion strain. Transmission of vCJD prions to Tg1014 mice resulted in 2 different strains, determined by neuropathology and biochemical analysis, which correlated with the length of the incubation time. One strain had the biochemical, neuropathological, and transmission characteristics, including longer incubation times, of the inoculated vCJD strain; the second strain produced a phenotype resembling that of sCJD prions including relatively shorter incubation periods. Mice with intermediate incubation periods for vCJD prions had a mixture of the 2 strains. Both strains were serially transmitted in Tg1014 mice, which led to further reduction in incubation periods. Conversion of vCJD-like to sCJD-like strains was favored in Tg1014 mice more than in the Tg22372 line. The single amino acid difference therefore appears to offer selective pressure for propagation of the sCJD-like strain.These 2 Tg mouse lines provide relatively rapid models to study human prion diseases as well as the evolution of human prion strains.

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Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein.

Publications

Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein.

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