Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein

Brent Race,Casper Jansen,Katie Williams,Piero Parchi,Andrew G Hughson,Annemieke J M Rozemuller,Bruce Chesebro

doi:10.1186/s40478-018-0516-2

Abstract

Human familial prion diseases are associated with mutations at 34 different prion protein (PrP) amino acid residues. However, it is unclear whether infectious prions are found in all cases. Mutant PrP itself may be neurotoxic, or alternatively, PrP mutation might predispose to spontaneous formation of infectious PrP isoforms. Previous reports demonstrated transmission to animal models by human brain tissue expressing 7 different PrP mutations, but 3 other mutations were not transmissible. In the present work, we tested transmission using brain homogenates from patients expressing 3 untested PrP mutants: G131V, Y226X, and Q227X. Human brain homogenates were injected intracerebrally into tg66 transgenic mice overexpressing human PrP. Mice were followed for nearly 800 days.From 593 to 762 dpi, 4 of 8 mice injected with Y226X brain had PrPSc detectable in brain by immunostaining, immunoblot, and PrP amyloid seeding activity assayed by RT-QuIC. From 531 to 784 dpi, 11 of 11 G131V-injected mice had PrPSc deposition in brain, but none were positive by immunoblot or RT-QuIC assay. In contrast, from 529 to 798 dpi, no tg66 mice injected with Q227X brain had PrPSc or PrP amyloid seeding activity detectable by these methods. Y226X is the only one of 4 known PrP truncations associated with familial disease which has been shown to be transmissible. This transmission of prion infectivity from a patient expressing truncated human PrP may have implications for the spread and possible transmission of other aggregated truncated proteins in prion-like diseases such as Alzheimer’s disease, Parkinson’s disease and tauopathies.

Highlights

Prion diseases are rare fatal neurodegenerative diseases of humans and animals which are transmissible by exposure to diseased tissues via ingestion, injection or transplantation
Prion diseases can be divided into several categories based on presumed etiologies [5, 11]: sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic CJD associated with injection or grafting of infected tissue, variant CJD associated with exposure to bovine spongiform encephalopathy (BSE)
In Gerstmann-SträusslerScheinker disease (GSS) and prion protein (PrP)-cerebral amyloid angiopathy (CAA), immunoblotting reveals proteinase K (PK)-resistant PrP bands approximately 7–8 kD in size which correlate with the presence of amyloid PrP scrapie (PrPSc) and are distinct from the larger bands usually seen in genetic CJD or fatal familial insomnia (FFI) [31, 33, 42]

Summary

Introduction

Prion diseases are rare fatal neurodegenerative diseases of humans and animals which are transmissible by exposure to diseased tissues via ingestion, injection or transplantation These diseases are often characterized by spongiform degeneration or vacuolation of gray matter, astrogliosis and microgliosis, and deposition of a partially proteinase K-resistant diseaseassociated form of the normal host prion protein (PrP) [5, 24]. A similar prion-like seeded polymerization mechanism appears to be responsible for the formation of protein aggregates involving α-synuclein, Aβ and tau in Parkinson’s disease, Alzheimer’s disease, and tauopathies [13, 48]. Genetic prion diseases usually display prolonged clinical course, variable spongiform degeneration, variation in the molecular size of PrP detected in disease-associated deposits, and presence of abnormal PrP in an amyloid form. In GSS and PrP-CAA, immunoblotting reveals proteinase K (PK)-resistant PrP bands approximately 7–8 kD in size which correlate with the presence of amyloid PrPSc and are distinct from the larger bands usually seen in genetic CJD or FFI [31, 33, 42]

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