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Bioluminescence Imaging of Neuroinflammation in Transgenic Mice After Peripheral Inoculation of Alpha-Synuclein Fibrils
Published on: April 13, 2017
Transgenic mouse models expressing human and macaque prion protein exhibit similar prion susceptibility on a
Juan Carlos Espinosa1, Emmanuel E Comoy2, Alba Marin-Moreno3
1Centro de Investigación en Sanidad Animal (INIA-CISA), 28130, Valdeolmos, Madrid, Spain. espinosa.juan@inia.es.
Abstract:
Cynomolgus macaque has been used for the evaluation of the zoonotic potential of prion diseases, especially for classical-Bovine Spongiform Encephalopathy (classical-BSE) infectious agent. PrP amino acid sequence is considered to play a key role in the susceptibility to prion strains and only one amino acid change may alter this susceptibility. Macaque and human-PrP sequences have only nine amino acid differences, but the effect of these amino acid changes in the susceptibility to dissimilar prion strains is unknown. In this work, the transmissibility of a panel of different prions from several species was compared in transgenic mice expressing either macaque-PrPC (TgMac) or human-PrPC (Hu-Tg340). Similarities in the transmissibility of most prion strains were observed suggesting that macaque is an adequate model for the evaluation of human susceptibility to most of the prion strains tested. Interestingly, TgMac were more susceptible to classical-BSE strain infection than Hu-Tg340. This differential susceptibility to classical-BSE transmission should be taken into account for the interpretation of the results obtained in macaques. It could notably explain why the macaque model turned out to be so efficient (worst case model) until now to model human situation towards classical-BSE despite the limited number of animals inoculated in the laboratory experiments.
Insights
Transgenic mice expressing macaque PrP (TgMac) showed similar prion disease susceptibility to human PrP (Hu-Tg340) models, except for enhanced classical-Bovine Spongiform Encephalopathy (classical-BSE) susceptibility in TgMac.
Area of Science:
- Neuroscience
- Infectious Diseases
- Genetics
Background:
- Cynomolgus macaques are used to study prion disease zoonotic potential, particularly classical-Bovine Spongiform Encephalopathy (classical-BSE).
- Prion protein (PrP) amino acid sequence influences susceptibility to prion strains; minor changes can significantly alter this.
- Nine amino acid differences exist between macaque and human PrP, but their impact on prion strain susceptibility is not fully understood.
Purpose of the Study:
- To compare the transmissibility of various prion strains in transgenic mice expressing macaque PrP (TgMac) versus human PrP (Hu-Tg340).
- To evaluate the macaque model's adequacy for assessing human susceptibility to different prion strains.
Main Methods:
- Generation of transgenic mouse lines expressing either macaque PrP (TgMac) or human PrP (Hu-Tg340).
- Inoculation of these transgenic mice with a panel of prion strains from diverse species.
- Comparative analysis of prion strain transmissibility and incubation periods between TgMac and Hu-Tg340 models.
Main Results:
- Most prion strains exhibited similar transmissibility in both TgMac and Hu-Tg340 mice.
- TgMac mice demonstrated significantly higher susceptibility to the classical-BSE strain compared to Hu-Tg340 mice.
- This differential susceptibility highlights a key difference in classical-BSE transmission between the models.
Conclusions:
- The macaque model is generally suitable for evaluating human susceptibility to most tested prion strains.
- TgMac mice exhibit heightened susceptibility to classical-BSE, suggesting this may explain the macaque model's past efficiency in predicting human risk.
- Findings necessitate careful interpretation of macaque model results concerning classical-BSE, considering its 'worst-case model' potential.
