PrP<sup>Sc</sup>-specific antibodies do not induce prion disease or misfolding of PrP<sup>C</sup>in highly susceptible Tga20 mice

Määttänen, Pekka; Taschuk, Ryan; Ross, Li; Marciniuk, Kristen; Bertram, Lisa; Potter, Andrew; Cashman, Neil R.; Napper, Scott

doi:10.4161/pri.26639

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…67 Within this sensitive model, mice received the optimized YYR-based vaccine and were probed for deposition of PK-resistant material more than 8.5 mo post vaccination. 68 These mice, and their unvaccinated, age-matched controls, remained healthy with no abnormal behavior within the testing period of 255 d post-immunization (311 d of age) (Fig. 5D).…”

Section: Safety Of Induced Immune Responsesmentioning

confidence: 85%

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Taschuk

Marciniuk

Määttänen

et al. 2014

Prion

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Prions are a novel form of infectivity based on the misfolding of a self-protein (PrP(C)) into a pathological, infectious isomer (PrP(Sc)). The current uncontrolled spread of chronic wasting disease in cervids, coupled with the demonstrated zoonotic nature of select livestock prion diseases, highlights the urgent need for disease management tools. While there is proof-of-principle evidence for a prion vaccine, these efforts are complicated by the challenges and risks associated with induction of immune responses to a self-protein. Our priority is to develop a PrP(Sc)-specific prion vaccine based on epitopes that are uniquely exposed upon misfolding. These disease specific epitopes (DSEs) have the potential to enable specific targeting of the pathological species through immunotherapy. Here we review outcomes of the translation of a prion DSE into a PrP(Sc)-specific vaccine based on the criteria of immunogenicity, safety and specificity.

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Section: Safety Of Induced Immune Responsesmentioning

confidence: 85%

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Taschuk

Marciniuk

Määttänen

et al. 2014

Prion

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“…The next three columns list the number of peptides that were significantly (P < 0.2) hyper-and hypo-phosphorylated based on the kinome analysis in female and male mice. The last column lists the number of hyper-or hypophosphorylated peptides that were in common in both sexes (FC) > ± 1 (Goel et al 2018;Maattanen et al 2013). The P-value of 0.2 was chosen as it is known that if the threshold were to be too conservative, then the likelihood of false negatives would increase, and if too relaxed, then the analysis might provide false positives.…”

Section: Discussionmentioning

confidence: 99%

A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

et al. 2020

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The R6/2 transgenic mouse model of Huntington’s disease (HD) carries several copies of exon1 of the huntingtin gene that contains a highly pathogenic 120 CAG-repeat expansion. We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6/2 mice at a pre-symptomatic (e.g., embryonic) and symptomatic (e.g., between 3 and 10 weeks postnatal) time points. We identified changes in several signaling cascades, for example, the Akt/FoxO3/CDK2, mTOR/ULK1, and RAF/MEK/CREB pathways. We also identified the Rho-Rac GTPase cascade that contributes to cytoskeleton organization through modulation of the actin-binding proteins, cofilin and profilin. Immunoblotting revealed higher levels of phosphoSer138-profilin in embryonic R6/2 mouse samples (cf. WT mice) that diminish progressively and significantly over the postnatal, symptomatic course of the disease. We detected sex- and genotype-dependent patterns in the phosphorylation of actin-regulators such a ROCK2, PAK, LIMK1, cofilin, and SSH1L, yet none of these aligned consistently with the changing levels of phosphoSer138-profilin. This could be reflecting an imbalance in the sequential influences these regulators are known to exert on actin signaling. The translational potential of these observations was inferred from preliminary observations of changes in LIMK-cofilin signaling and loss of neurite integrity in neural stem cells derived from an HD patient (versus a healthy control). Our observations suggest that a pre-symptomatic, neurodevelopmental onset of change in the phosphorylation of Ser138-profilin, potentially downstream of distinct signaling changes in male and female mice, could be contributing to cytoskeletal phenotypes in the R6/2 mouse model of HD pathology.

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“…Similarly, prolonged incubation of brain homogenates with polyclonal antibodies to the three DSEs failed to generate PrP Sc (64,66). Finally, induction of high titre PrP Sc -specific antibodies in prion-disease sensitized transgenic mice did not result in clinical nor biochemical indications of prion disease after eight months (70).…”

Section: Potential Dangers Of Prp Sc Reactivitymentioning

confidence: 95%

Oral vaccination as a potential strategy to manage chronic wasting disease in wild cervid populations

Napper

Schätzl

2023

Front. Immunol.

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Prion diseases are a novel class of infectious disease based in the misfolding of the cellular prion protein (PrPC) into a pathological, self-propagating isoform (PrPSc). These fatal, untreatable neurodegenerative disorders affect a variety of species causing scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jacob disease (CJD) in humans. Of the animal prion diseases, CWD is currently regarded as the most significant threat due its ongoing geographical spread, environmental persistence, uptake into plants, unpredictable evolution, and emerging evidence of zoonotic potential. The extensive efforts to manage CWD have been largely ineffective, highlighting the need for new disease management tools, including vaccines. Development of an effective CWD vaccine is challenged by the unique biology of these diseases, including the necessity, and associated dangers, of overcoming immune tolerance, as well the logistical challenges of vaccinating wild animals. Despite these obstacles, there has been encouraging progress towards the identification of safe, protective antigens as well as effective strategies of formulation and delivery that would enable oral delivery to wild cervids. In this review we highlight recent strategies for antigen selection and optimization, as well as considerations of various platforms for oral delivery, that will enable researchers to accelerate the rate at which candidate CWD vaccines are developed and evaluated.

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PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Cited by 9 publications

References 29 publications

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

Oral vaccination as a potential strategy to manage chronic wasting disease in wild cervid populations

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PrPSc-specific antibodies do not induce prion disease or misfolding of PrPCin highly susceptible Tga20 mice

Cited by 9 publications

References 29 publications

Safety, specificity and immunogenicity of a PrPSc-specific prion vaccine based on the YYR disease specific epitope

Safety, specificity and immunogenicity of a PrPSc-specific prion vaccine based on the YYR disease specific epitope

A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

Oral vaccination as a potential strategy to manage chronic wasting disease in wild cervid populations

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Product

Resources

About

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope