TY  - JOUR
AU  - Mehra, Surabhi
AU  - Bourkas, Matthew Ec
AU  - Kaczmarczyk, Lech
AU  - Stuart, Erica
AU  - Arshad, Hamza
AU  - Griffin, Jennifer K
AU  - Frost, Kathy L
AU  - Walsh, Daniel J
AU  - Supattapone, Surachai
AU  - Booth, Stephanie A
AU  - Jackson, Walker Scot
AU  - Watts, Joel C
TI  - Convergent generation of atypical prions in knockin mouse models of genetic prion disease.
JO  - The journal of clinical investigation
VL  - 134
IS  - 15
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2024-00945
SP  - e176344
PY  - 2024
AB  - Most 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.
KW  - Animals
KW  - Mice
KW  - Prion Diseases: genetics
KW  - Prion Diseases: pathology
KW  - Prion Diseases: metabolism
KW  - Gene Knock-In Techniques
KW  - Disease Models, Animal
KW  - Mice, Transgenic
KW  - Prion Proteins: genetics
KW  - Prion Proteins: metabolism
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Mutation, Missense
KW  - Humans
KW  - Arvicolinae: genetics
KW  - Arvicolinae: metabolism
KW  - Amino Acid Substitution
KW  - Prions: genetics
KW  - Prions: metabolism
KW  - Protein Folding
KW  - Neurodegeneration (Other)
KW  - Neuroscience (Other)
KW  - Prions (Other)
KW  - Prion Proteins (NLM Chemicals)
KW  - Prions (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39087478
C2  - pmc:PMC11291267
DO  - DOI:10.1172/JCI176344
UR  - https://pub.dzne.de/record/271073
ER  -