Browsing by Person "Jeffrey, Martin"

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Mechanism of PrP-Amyloid Formation in Mice Without Transmissible Spongiform Encephalopathy
(Wiley, 2011-06-03) Jeffrey, Martin; McGovern, Gillian; Chambers, Emily V.; King, Declan; Gonzalez, Lorenzo; Manson, Jean C.; Ghetti, Bernardino; Piccardo, Pedro; Barron, Rona
Gerstmann–Sträussler–Scheinker (GSS) P102L disease is a familial form of a transmissible spongiform encephalopathy (TSE) that can present with or without vacuolation of neuropil. Inefficient disease transmission into 101LL transgenic mice was previously observed from GSS P102L without vacuolation. However, several aged, healthy mice had large plaques composed of abnormal prion protein (PrPd). Here we perform the ultrastructural characterization of such plaques and compare them with PrPd aggregates found in TSE caused by an infectious mechanism. PrPd plaques in 101LL mice varied in maturity, with some being composed of deposits without visible amyloid fibrils. PrPd was present on cell membranes in the vicinity of all types of plaques. In contrast to the unicentric plaques seen in infectious murine scrapie, the plaques seen in the current model were multicentric and were initiated by protofibrillar forms of PrPd situated on oligodendroglia, astrocytes and neuritic cell membranes. We speculate that the initial conversion process leading to plaque formation begins with membrane-bound PrPC but that subsequent fibrillization does not require membrane attachment. We also observed that the membrane alterations consistently seen in murine scrapie and other infectious TSEs were not present in 101LL mice with plaques, suggesting differences in the pathogenesis of these conditions.
Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aβ and mutated human Alzheimer's precursor protein (APP)
(Wiley, 2014-08-18) Jeffrey, Martin; McGovern, Gillian; Barron, Rona; Baumann, Frank
Alzheimer's disease and the transmissible spongiform encephalopathies or prion diseases accumulate misfolded and aggregated forms of neuronal cell membrane proteins. Distinctive membrane lesions caused by the accumulation of disease-associated prion protein (PrPd) are found in prion disease but morphological changes of membranes are not associated with Aβ in Alzheimer's disease. Membrane changes occur in all prion diseases where PrPd is attached to cell membranes by a glycosyl-phosphoinositol (GPI) anchor but are absent from transgenic mice expressing anchorless PrPd. Here we investigate whether GPI membrane attached Aβ may also cause prion-like membrane lesions.
Molecular Model of Prion Transmission to Humans
(Centers for Disease Control and Prevention, 2009-12) Jones, Michael; Wight, Darren; Barron, Rona; Jeffrey, Martin; Manson, Jean; Prowse, Christopher; Ironside, James W.; Head, Mark W.
To assess interspecies barriers to transmission of transmissible spongiform encephalopathies, we investigated the ability of disease-associated prion proteins (PrPd) to initiate conversion of the human normal cellular form of prion protein of the 3 major PRNP polymorphic variants in vitro. Protein misfolding cyclic amplification showed that conformation of PrPd partly determines host susceptibility.
PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions
(Springer Nature, 2016-06-26) Barron, Rona; King, Declan; Jeffrey, Martin; McGovern, Gillian; Agarwal, Sonya; Gill, Andrew C.; Piccardo, Pedro
Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the “prion-like” spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed fibrils may, therefore, more closely resemble a seeded proteinopathy than an infectious TSE disease.