Abstract
While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion infection in mice overexpressing a mutated prion protein (PrP) carrying a specific amino acid substitution characteristic of canids. Here, we show that coexpression of this mutated PrP and wild-type mouse PrP in transgenic mice inoculated with different mouse-adapted prion strains (22L, ME7, RML, and 301C) significantly increases survival times (by 45 to 113%). These data indicate that this amino acid substitution confers a dominant-negative effect on PrP, attenuating the conversion of PrPC to PrPSc and delaying disease onset without altering the neuropathological properties of the prion strains. Taken together, these findings have important implications for the development of new treatment approaches for prion diseases based on dominant-negative proteins.
Highlights
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative diseases of animals and humans that can be sporadic, genetic, or acquired by infection [1]
Three different transgenic mouse models were used in the present study: 1) Tga20 x Tga20 mice expressing mouse PrPC at a levels ∼8-fold higher than those observed in the mouse brain [21]; Tga20 x Prnp0/0 [22]
Certain prion protein (PrP) polymorphisms are strongly linked to susceptibility/resistance to prion diseases
Summary
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative diseases of animals and humans that can be sporadic (putatively spontaneous), genetic, or acquired by infection [1]. TSEs are caused by the accumulation of a misfolded protein, the scrapie-associated prion protein (PrPSc), which is produced by posttranslational conversion of the physiologically expressed cellular prion protein (PrPC) via an unknown mechanism. This abnormal form of the protein is protease resistant and is composed almost entirely of β-sheet structures [2,3,4,5]. The absence of prion diseases in other mammals exposed to contaminated food, including rabbits, equids, and canids, suggested the existence of prion-resistant species [15]. To identify the specific features of canine PrPC that account for its strong resistance to misfolding, we previously generated a transgenic mouse model expressing a PrP variant (N158D PrP), containing a single specific amino acid substitution, characteristic of the dog PrPC [Fernández-
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