Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

Piccardo, Pedro; King, Declan; Telling, Glenn C.; Manson, Jean; Barron, Rona

doi:10.1128/jvi.00673-13

Cited by 24 publications

(32 citation statements)

References 39 publications

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“…Insights might also emerge from an analysis of senescent nonhuman primates which, despite substantial accumulation of human-sequence Aβ with age, exhibit neither significant tauopathy nor dementia (Rosen et al, 2016). A possible parallel in the prion field is the dissociation of PrP-amyloid seeding and transmission of spongiform encephalopathy in a mouse model (Piccardo et al, 2013). …”

Section: Prion-like Properties Of Aβ: Open Questionsmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer disease. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins: Aβ protein in plaques and tau protein in tangles. At the molecular level, both proteins in a pathogenic state share key properties with classic prions, i.e., they consist of alternatively folded, β-sheet-rich forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the endogenous, sequential corruption of Aβ and then tau. Therapeutic options include reducing the production or multimerization of the proteins, uncoupling the Aβ-tauopathy connection, or promoting the inactivation or removal of anomalous assemblies from the brain. Although aberrant Aβ appears to be the prime mover of Alzheimer disease pathogenesis, once set in motion by Aβ, the prion-like propagation of tauopathy may proceed independently of Aβ; if so, Aβ might be solely targeted as an early preventive measure, but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both pathways.

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Section: Prion-like Properties Of Aβ: Open Questionsmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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“…Animal models can be precisely monitored from the time the agent is inoculated through advanced illness, facilitating study of both latent and overt phases of disease. We have shown that amyloid plaques containing PrP can form in mouse brains in the absence of infectivity detectable by inoculation of highly susceptible animals, suggesting that not all misfolded PrP is infectious in these experimental paradigms 14,15,16,17 . Thus, proteinopathies sharing some similarities to AD and PD occur in brains of mice when PrP misfolds.…”

Section: Animal Modelsmentioning

confidence: 95%

“…The severe tauopathy seen in squirrel monkeys infected with classical SQ-BSE 19 led us to study a line of transgenic mice from which the murine PRNP gene was deleted and then engineered to express a bovine PrP with a six-octapeptide repeat region ("bovinized knock-in" B6 mice) 28 ; we analyzed B6 mice intracerebrally inoculated with classical BSE agent from a bovine brain and also analyzed B6 mice inoculated with brain suspensions from cattle with two atypical forms of BSE: "heavy" or H-type BSE and bovine amyloidogenic spongiform encephalopathy (also called "light" or L-type BSE) 29 . To study possible correlation between PrP amyloid and p-tau, we used the following models: (i) wildtype (Wt) VM mice (an inbred Wt line of mice with known susceptibility to scrapie) inoculated intracerebrally with 87V mouse-adapted scrapie agent (87V-VM) 30,32 ; (ii) transgenic mice overexpressing mutant PrP-101L (equivalent to a mutation found in Gerstamann-Sträussler-Scheinker disease, GSS-22) that spontaneously develop a severe spongiform degeneration with abundant diffuse and amyloid PrP deposits in most areas of the central nervous system 17,27 ; and (iii) knock-in mice expressing a murine mutant PrP (101LL, corresponding to human PRNP P102L) inoculated with recombinant wild-type PrP (recWt-PrP) or recombinant mutant PrP (recPrP-101L) fibrils 33 . To study p-tau accumulation in animals with large amounts of widespread diffuse nonamyloid PrP TSE deposits, we inoculated Wt C57BL mice with ME7 mouse-adapted scrapie agent (ME7-C57BL) 30 .…”

Section: P-tau In Rodents With Prp Accumulationmentioning

confidence: 99%

Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies

Piccardo

Asher

2018

Arq. Neuro-Psiquiatr.

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Protein misfolding diseases are usually associated with deposits of single “key” proteins that somehow drive the pathology; β-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered “complex” proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of “secondary proteins”) infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.

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“…Also, PrP Sc is stable only in its aggregated form that can “seed” polymerization of additional PrP C , thus converting it into additional PrP Sc . Further, more definitive work combining studies in Tg(GSS) and Prnp gene-targeted 101LL mice indicated that clinical or profound neuropathological changes were absent in gene targeted mice inoculated with brain extracts of spontaneously sick Tg(GSS) mice, indicating that de novo formation of abnormally aggregated PrP in the host does not always result in a transmissible prion disease [98]. In a related issue, the role of PrP overexpression in the production and transmission of synthetic mammalian prions (SMP) [99] originating from E. coli-derived recombinant MoPrP remains to be determined.…”

Section: Prion Transmission Barriersmentioning

confidence: 99%

Insights into Mechanisms of Transmission and Pathogenesis from Transgenic Mouse Models of Prion Diseases

Moreno

Telling

2017

Methods in Molecular Biology

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Prions represent a new paradigm of protein-mediated information transfer. In the case of mammals, prions are the cause of fatal, transmissible neurodegenerative diseases, sometimes referred to as transmissible spongiform encephalopathies (TSE’s), which frequently occur as epidemics. An increasing body of evidence indicates that the canonical mechanism of conformational corruption of cellular prion protein (PrPC) by the pathogenic isoform (PrPSc) that is the basis of prion formation in TSE’s, is common to a spectrum of proteins associated with various additional human neurodegenerative disorders, including the more common Alzheimer’s and Parkinson’s diseases. The peerless infectious properties of TSE prions, and the unparalleled tools for their study, therefore enable elucidation of mechanisms of template-mediated conformational propagation that are generally applicable to these related disease states. Many unresolved issues remain including the exact molecular nature of the prion, the detailed cellular and molecular mechanisms of prion propagation, and the means by which prion diseases can be both genetic and infectious. In addition, we know little about the mechanism by which neurons degenerate during prion diseases. Tied to this, the physiological role of the normal form of the prion protein remains unclear and it is uncertain whether or not loss of this function contributes to prion pathogenesis. The factors governing the transmission of prions between species remain unclear, in particular the means by which prion strains and PrP primary structure interact to affect inter-species prion transmission. Despite all these unknowns, advances in our understanding of prions have occurred because of their transmissibility to experimental animals and the development of transgenic (Tg) mouse models has done much to further our understanding about various aspects of prion biology. In this review we will focus on advances in our understanding of prion biology that occurred in the past eight years since our last review of this topic.

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Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

Cited by 24 publications

References 39 publications

Prion-like mechanisms in Alzheimer disease

Prion-like mechanisms in Alzheimer disease

Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies

Insights into Mechanisms of Transmission and Pathogenesis from Transgenic Mouse Models of Prion Diseases

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