The role of the prion protein membrane anchor in prion infection

Priola, Suzette A.; McNally, Kristin L.

doi:10.4161/pri.3.3.9771

Cited by 34 publications

(20 citation statements)

References 42 publications

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“…56 Thus, in vitro, the presence of PrP C at the cell surface is a prerequisite for efficient conversion to PrP Sc . 57 Taken together, these reports indicate that PrP C localization in lipid raft-enriched domains is of high importance for prion conversion. Interestingly, only when the amyloidogenic yeast protein Sup35 is attached to a GPI-anchor, it can be propagated to neighboring cells and these cells can then sustain and propagate the aggregates for many passages.…”

mentioning

confidence: 83%

The GPI-anchoring of PrP

Puig

Altmeppen

Glatzel

2014

Prion

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mentioning

confidence: 83%

The GPI-anchoring of PrP

Puig

Altmeppen

Glatzel

2014

Prion

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“…Cell culture and transgenic-mouse studies have established that the C-terminal GPI anchor is not required for PrP RES formation but is necessary for PrP RES propagation between cells and for cytopathology (28). Altering the location of PrP C from the cell surface to the transmembrane domain prevents PrP C conversion (5,29,30).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro

Hoover

Davenport

Henderson

et al. 2017

J Virol

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The normal cellular prion protein (PrP C ) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time quaking-induced conversion (RTQuIC). Using an alcohol-based extraction technique, we removed the lipid content from chronic wasting disease (CWD)-infected white-tailed deer brain homogenates and found that lipid extraction enabled RT-QuIC detection of CWD prions in a 2-log 10 -greater concentration of brain sample. Conversely, addition of brain-derived lipid extracts to CWD prion brain or lymph node samples inhibited amyloid formation in a dose-dependent manner. Subsequent lipid analysis demonstrated that this inhibitory function was restricted to the polar lipid fraction in brain. We further investigated three phospholipids commonly found in lipid membranes, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol, and found all three similarly inhibited RT-QuIC. These results demonstrating polar-lipid, and specifically phospholipid, inhibition of prion-seeded amyloid formation highlight the diverse roles lipid constituents may play in the prion conversion process. IMPORTANCE Prion conversion is likely influenced by lipid interactions, given the location of normal prion protein (PrP C ) in lipid rafts and lipid cofactors generating infectious prions in in vitro models. Here, we use real-time quaking-induced conversion (RT-QuIC) to demonstrate that endogenous brain polar lipids can inhibit prionseeded amyloid formation, suggesting that prion conversion is guided by an environment of proconversion and anticonversion lipids. These experiments also highlight the applicability of RT-QuIC to identify potential therapeutic inhibitors of prion conversion.

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“…The disease resistance of this mutant has stimulated research into the impact of GPIanchoring on prion trafficking and disease progression, both in vitro and in vivo. [39] In vivo genetic screens Not surprisingly, genetic methods have proven to be powerful for identifying genes involved in GPI-related processes. Genetic screens have been a major tool in elucidating the GPI biosynthetic pathway, as well as discovering the subunits of GPI-T, typically in combination with other techniques like lipid profiling by thin-layer chromatography (TLC).…”

Section: In Vivo Methodsmentioning

confidence: 99%

“…Prion diseases are neurodegenerative conditions propagated by abnormal misfolded prion protein (PrP C is susceptible to phospholipase digestion; this indicates that the conformational change results in obstruction of the phospholipase cleavage site. [113] Although the GPI anchor is believed to exert significant influence on prion infectivity, [39] conflicting results make the impact of the GPI anchor unclear. Cells expressing anchorless PrP were resistant to persistent scrapie infection in vitro, although some PrP Sc was detected within the first 96 h of infection.…”

mentioning

confidence: 99%