Journal Article

DZNE-2024-00945

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Convergent generation of atypical prions in knockin mouse models of genetic prion disease.

Mehra, S. ; Bourkas, M. E. ; Kaczmarczyk, L.DZNE* ; Stuart, E. ; Arshad, H. ; Griffin, J. K. ; Frost, K. L. ; Walsh, D. J. ; Supattapone, S. ; Booth, S. A. ; Jackson, W. S.DZNE* ; Watts, J. C.

2024
ASCJ Ann Arbor, Mich.

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Please use a persistent id in citations: doi:10.1172/JCI176344

Abstract: 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.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Prion Diseases: genetics (MeSH) ; Prion Diseases: pathology (MeSH) ; Prion Diseases: metabolism (MeSH) ; Gene Knock-In Techniques (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Transgenic (MeSH) ; Prion Proteins: genetics (MeSH) ; Prion Proteins: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Mutation, Missense (MeSH) ; Humans (MeSH) ; Arvicolinae: genetics (MeSH) ; Arvicolinae: metabolism (MeSH) ; Amino Acid Substitution (MeSH) ; Prions: genetics (MeSH) ; Prions: metabolism (MeSH) ; Protein Folding (MeSH) ; Neurodegeneration ; Neuroscience ; Prions ; Prion Proteins ; Prions

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Contributing Institute(s):

1. Selective Vulnerability of Neurodegenerative Diseases (AG Jackson)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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