Crucial Role for Prion Protein Membrane Anchoring in the Neuroinvasion and Neural Spread of Prion Infection

Klingeborn, Mikael; Race, Brent; Meade-White, Kimberly; Rosenke, Rebecca; Striebel, James F.; Chesebro, Bruce

doi:10.1128/jvi.02167-10

Cited by 51 publications

(64 citation statements)

References 60 publications

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“…Importantly, however, infectious prionosis can be induced in mice expressing anchorless secreted PrP (30). Although GPIanchoring might facilitate CNS neuroinvasion of TSE agents (31), our data clearly show that membrane-anchoring is not a requirement for infectious properties of protein aggregates.…”

Section: Discussionmentioning

confidence: 61%

Cell-to-cell propagation of infectious cytosolic protein aggregates

Hofmann

Denner

Nussbaum-Krammer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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Prions are self-templating protein conformers that replicate by recruitment and conversion of homotypic proteins into growing protein aggregates. Originally identified as causative agents of transmissible spongiform encephalopathies, increasing evidence now suggests that prion-like phenomena are more common in nature than previously anticipated. In contrast to fungal prions that replicate in the cytoplasm, propagation of mammalian prions derived from the precursor protein PrP is confined to the cell membrane or endocytic vesicles. Here we demonstrate that cytosolic protein aggregates can also behave as infectious entities in mammalian cells. When expressed in the mammalian cytosol, protein aggregates derived from the prion domain NM of yeast translation termination factor Sup35 persistently propagate and invade neighboring cells, thereby inducing a self-perpetuating aggregation state of NM. Cell contact is required for efficient infection. Aggregates can also be induced in primary astrocytes, neurons, and organotypic cultures, demonstrating that this phenomenon is not specific to immortalized cells. Our data have important implications for understanding prion-like phenomena of protein aggregates associated with human diseases and for the growing number of amyloidogenic proteins discovered in mammals.

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Section: Discussionmentioning

confidence: 61%

Cell-to-cell propagation of infectious cytosolic protein aggregates

Hofmann

Denner

Nussbaum-Krammer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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“…PrPres was detected as described previously (15). In brief, PrPres antigen was retrieved in a Ventana automated Discovery XT stainer by incubation for 188 min at 95°C in CC1 buffer (Ventana) containing Trisborate-EDTA (pH 8.0), followed by (i) staining of PrPres with the monoclonal human anti-mouse PrP antibody D13 (dilution, 1:500) (InPro Biotechnology, South San Francisco, CA) at 37°C for 2 h, (ii) secondary staining with biotinylated anti-human IgG (dilution, 1:250) (Jackson ImmunoResearch, West Grove, PA), and (iii) avidin-horseradish peroxidase (HRP) and chromogen development with a DAB Map kit (Ventana).…”

Section: Methodsmentioning

confidence: 99%

Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

Tribouillard-Tanvier

Race

Striebel

et al. 2012

J Virol

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Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease. Here, in time course studies of C57BL/10 mice intracerebrally inoculated with 22L scrapie, abnormal protease-resistant prion protein (PrPres), astrogliosis, and microgliosis were first detected at 40 days after intracerebral scrapie inoculation. In cytokine studies, IL-12p40 was first elevated by 60 days; CCL3, IL-1␤, and CXCL1 were elevated by 80 days; and CCL2 and CCL5 were elevated by 115 days. IL12p40 showed the most extensive increase throughout disease and was 30-fold above control levels at the terminal stage. Because of the early onset and dramatic elevation of IL-12p40 during scrapie, we investigated whether IL-12p40 contributed to the development of prion disease neuropathogenesis by using three different scrapie strains (22L, RML, 79A) to infect knockout mice in which the gene encoding IL-12p40 was deleted. We also studied knockout mice lacking IL-12p35, which combines with IL-12p40 to form active IL-12 heterodimers. In all instances, knockout mice did not differ from control mice in survival time, clinical tempo, or levels of spongiosis, gliosis, or PrPres in the brain. Thus, neither IL-12p40 nor IL-12p35 molecules were required for prion disease-associated neurodegeneration or neuroinflammation. P rion diseases, also known as transmissible spongiform encephalopathy (TSE) diseases, are infectious neurodegenerative disorders that affect both humans and animals (24). Prion diseases are characterized by spongiform degeneration of gray matter, gliosis, and accumulation of a misfolded, partially protease resistant form, PrPres (also known as PrP Sc ), of the normal cellular prion protein, PrPsen (also known as PrP C ). Activation and/or proliferation of astroglia and microglia is prominent during prion disease pathogenesis. Microglial and astroglial cells produce inflammatory mediators such as cytokines and chemokines in various neurodegenerative and infectious diseases, and all may contribute to the inflammation in prion disease (5,7,9,18,25,27,35). This neuroinflammatory reaction appears to be a host response to PrPres accumulation and associated brain cell damage. However, this neuroinflammation might also act either to increase or to decrease prion disease pathogenesis, and if so, therapeutic intervention to increase or dampen this reaction might be beneficial.Our previous study focused on the cytokine response in vitro in glial cells and in vivo in the brains of sick mice after scrapie infection (35). Despite extensive gliosis during prion disease, scrapieinfected mice showed consistent significant elevation of ...

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“…First, they reduce the expression of GPI-anchored PrP C which is essential for efficient prion conversion in cell cultures, the development of prion diseases in mice models, and central nervous system invasion after peripheral prion infection. 4,8,9,[22][23][24] GPI-anchored PrP C is also a cell surface receptor for prion soluble oligomers and relay intracellular toxic signals. 10,11 Releasing PrP C from the cell Keywords: prion, neuroprotection, prion disease, Alzheimer disease, α-cleavage, β-cleavage, shedding, PrPN1…”

Section: Secreted Forms Of Prp C In Prion Diseasesmentioning

confidence: 99%