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000271073 1001_ $$aMehra, Surabhi$$b0
000271073 245__ $$aConvergent generation of atypical prions in knockin mouse models of genetic prion disease.
000271073 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2024
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000271073 520__ $$aMost cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.
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000271073 650_7 $$2Other$$aNeurodegeneration
000271073 650_7 $$2Other$$aNeuroscience
000271073 650_7 $$2Other$$aPrions
000271073 650_7 $$2NLM Chemicals$$aPrion Proteins
000271073 650_7 $$2NLM Chemicals$$aPrions
000271073 650_2 $$2MeSH$$aAnimals
000271073 650_2 $$2MeSH$$aMice
000271073 650_2 $$2MeSH$$aPrion Diseases: genetics
000271073 650_2 $$2MeSH$$aPrion Diseases: pathology
000271073 650_2 $$2MeSH$$aPrion Diseases: metabolism
000271073 650_2 $$2MeSH$$aGene Knock-In Techniques
000271073 650_2 $$2MeSH$$aDisease Models, Animal
000271073 650_2 $$2MeSH$$aMice, Transgenic
000271073 650_2 $$2MeSH$$aPrion Proteins: genetics
000271073 650_2 $$2MeSH$$aPrion Proteins: metabolism
000271073 650_2 $$2MeSH$$aBrain: metabolism
000271073 650_2 $$2MeSH$$aBrain: pathology
000271073 650_2 $$2MeSH$$aMutation, Missense
000271073 650_2 $$2MeSH$$aHumans
000271073 650_2 $$2MeSH$$aArvicolinae: genetics
000271073 650_2 $$2MeSH$$aArvicolinae: metabolism
000271073 650_2 $$2MeSH$$aAmino Acid Substitution
000271073 650_2 $$2MeSH$$aPrions: genetics
000271073 650_2 $$2MeSH$$aPrions: metabolism
000271073 650_2 $$2MeSH$$aProtein Folding
000271073 7001_ $$aBourkas, Matthew Ec$$b1
000271073 7001_ $$0P:(DE-2719)2810486$$aKaczmarczyk, Lech$$b2
000271073 7001_ $$aStuart, Erica$$b3
000271073 7001_ $$aArshad, Hamza$$b4
000271073 7001_ $$aGriffin, Jennifer K$$b5
000271073 7001_ $$aFrost, Kathy L$$b6
000271073 7001_ $$aWalsh, Daniel J$$b7
000271073 7001_ $$aSupattapone, Surachai$$b8
000271073 7001_ $$aBooth, Stephanie A$$b9
000271073 7001_ $$0P:(DE-2719)2810253$$aJackson, Walker Scot$$b10
000271073 7001_ $$aWatts, Joel C$$b11
000271073 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI176344$$gVol. 134, no. 15, p. e176344$$n15$$pe176344$$tThe journal of clinical investigation$$v134$$x0021-9738$$y2024
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