Novel Approaches to Fight Prion Diseases

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dc.contributor.advisorSchaetzl, Hermann M.
dc.contributor.authorThapa, Simrika
dc.contributor.committeememberGilch, Sabine
dc.contributor.committeememberTrang, Tuan
dc.contributor.committeemembervan Marle, Guido
dc.contributor.committeememberCoffin, Carla S.
dc.contributor.committeememberTelling, Glenn C.
dc.date2020-11
dc.date.accessioned2020-05-04T14:54:06Z
dc.date.available2020-05-04T14:54:06Z
dc.date.issued2020-04-29
dc.description.abstractPrion diseases are fatal neurodegenerative disorders caused by PrPSc, the misfolded and infectious isoform of the cellular prion protein (PrPC). Currently, no preventive or therapeutic measures are available. In this work, we focused on therapeutic and prophylactic strategies against prion infections. In the therapeutic approach, we targeted cellular pathways and investigated the role of the quality control (QC) proteins, ERp57 and VIP36, on prion propagation. We found that the overexpression of ERp57 or VIP36 significantly reduced PrPSc levels in persistently prion-infected cells and decreased the susceptibility of uninfected cells to de novo prion infection. Moreover, lentiviral-mediated overexpression of ERp57 prolonged the survival of prion-infected mice. Mechanistically, we found that ERp57 overexpression reduced endoplasmic reticulum (ER) stress. To translate this proof-of-concept into potential drug therapy, we investigated the anti-prion effect of Sephin1, shown to prolong the phosphorylation of eIF2α and lower ER stress in the cells. In persistently prion-infected neuronal cells, we found that treatment with Sephin1 markedly reduced PrPSc levels. Moreover, Sephin1 reduced ER stress-induced PrP aggregates in cells and significantly extended the survival of prion-infected mice. These data provide the basis for targeting these cellular pathways as novel anti-prion therapy. In our prophylactic approach, we hypothesized that active vaccination is useful to contain chronic wasting disease (CWD), a contagious and expanding prion disease of cervids. Here, we vaccinated transgenic mice expressing elk prion protein with adjuvant CpG alone, or one of four recombinant PrP (rPrP) immunogens: deer dimer (Ddi), deer monomer (Dmo), mouse dimer (Mdi), and mouse monomer (Mmo). After challenging the animals with CWD prions intraperitoneally, we found that all vaccinated groups had longer survival times than the CpG control group. Interestingly, the Mmo-immunized group revealed that survival was extended by 60%. We also observed 28.4% and 24.1% prolongation in Dmo and Ddi groups, respectively. Our preliminary study in reindeer showed substantial humoral immune response induced by Mdi and Ddi, and the sera from the Ddi-vaccinated reindeer significantly reduced CWD prions in a cell culture model. Taken together, this study describes potential vaccine candidates against CWD. However, their protective effect in the natural cervid host needs further investigation.en_US
dc.identifier.citationThapa, S. (2020). Novel Approaches to Fight Prion Diseases (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37788
dc.identifier.urihttp://hdl.handle.net/1880/111977
dc.language.isoengen_US
dc.publisher.facultyVeterinary Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectprion diseaseen_US
dc.subjectER quality controlen_US
dc.subjectER stressen_US
dc.subjectneurodegenerationen_US
dc.subjectSephin1en_US
dc.subjectchronic wasting diseaseen_US
dc.subjectvaccineen_US
dc.subjectprionen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationNeuroscienceen_US
dc.subject.classificationVeterinary Scienceen_US
dc.subject.classificationImmunologyen_US
dc.titleNovel Approaches to Fight Prion Diseasesen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineVeterinary Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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