Visualization of Prion Infection in Transgenic Mice Expressing Green Fluorescent Protein-Tagged Prion Protein

Barmada, S. J.

doi:10.1523/jneurosci.1192-05.2005

Cited by 46 publications

(47 citation statements)

References 40 publications

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“…These results suggest that prion infection might impair the post-Golgi trafficking of certain types of membrane proteins, causing neuronal dysfunctions associated with prion disease. Mice tg for the GPI-anchored membrane protein PrP-EGFP, a fusion protein of PrP with EGFP, were reported to exhibit aberrant accumulation of PrP-EGFP in the Golgi apparatus in neurons after infection with RML prions 9 . PrP-EGFP itself did not undergo conformational conversion and therefore failed to support prion propagation in mice 9 .…”

Section: Discussionmentioning

confidence: 99%

“…Mice tg for the GPI-anchored membrane protein PrP-EGFP, a fusion protein of PrP with EGFP, were reported to exhibit aberrant accumulation of PrP-EGFP in the Golgi apparatus in neurons after infection with RML prions 9 . PrP-EGFP itself did not undergo conformational conversion and therefore failed to support prion propagation in mice 9 . These results reinforce our conclusion that prion infection could disturb the post-Golgi trafficking of membrane proteins to the cell surface, inducing aberrant accumulation of them in the Golgi apparatus.…”

Section: Discussionmentioning

confidence: 99%

“…These results reinforce our conclusion that prion infection could disturb the post-Golgi trafficking of membrane proteins to the cell surface, inducing aberrant accumulation of them in the Golgi apparatus. Interestingly, accumulation of PrP-EGFP in the Golgi apparatus in the mice was observed from the early stages after infection 9 , suggesting that impairment of post-Golgi trafficking might be an early pathogenic event in prion disease. Consistent with this idea, we showed that the surface expression of IRa and PrP C was reduced in infected mouse brains well before the onset of clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…PrP Sc has been detected near the Golgi apparatus in prion-infected cells 8 . Transgenic (tg) mice expressing PrP fused with green fluorescent protein on the wild-type background, that is, tg(PrP-EGFP)/Prnp þ / þ mice, developed prion disease after intracerebral inoculation with RML prions, with progressive accumulation of PrP-EGFP in the Golgi apparatus of neurons from the early stages of the infection 9 . The transmembrane form of PrP, Ctm PrP, with the N terminus in the cytosol and C terminus in the ER lumen is neurotoxic, causing prion disease-like neurodegeneration in mice 10,11 .…”

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Prions disturb post-Golgi trafficking of membrane proteins

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Prions disturb post-Golgi trafficking of membrane proteins

et al. 2013

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“…PrP--Sc accumulates at each of these sites, as well as likely at 445 the Golgi apparatus (28 In Alzheimer's disease, amyloid beta (A--beta) accumulates and is associated with 619 neurodegeneration. Abeta results from proteolytic cleavage of amyloid precursor 620 protein (APP).…”

Section: Transmissible Spongiform Encephalopathymentioning

confidence: 99%

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Reddy

2017

Preprint

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A scientific theory or hypothesis is presented, in which mineral particles may play a pivotal role in the prion disease transmissible spongiform encephalopathy (TSE), and possibly also in other protein--misfolding diseases. Montmorillonite clay (Mte) and other minerals are known to bind to scrapie prion protein (PrP--Sc) in soil. The hypothesis is explored that, in transmissible spongiform encephalopathy, Mte or other mineral particles, upon contact with lipids, such as in the gut or at the cell plasma membrane, may interact with lipids or with lipid rafts. The minerals may catalyze formation of lipid vesicles, and might also be capable of inducing lipid raft clustering or other lipid raft or plasma membrane changes. Some of these lipid vesicles or rafts might then contain or bind PrP--Sc, and sometimes also contain montmorillonite or the mineral catalyst. Mte--PrP--Sc or the affected lipid vesicles/particles could also promote PrP--C to PrP--Sc conversion by providing conditions for misfolding. These conditions provided for protein misfolding may include the following: multiple unique compartments providing sizes, shapes or aqueous/lipid environments that promote varied folding conformations, presence of an anion (Mte), negative--charge (Mte), lipid membrane mimetic (e.g. associated lipid particle, vesicle or raft), interaction with bound or contained PrP--Sc, presence of bound copper, and/or copper binding affinity. Mte--catalyzed lipid vesicles are proto--cell--like entities, making them potential candidates to be part of the infectious particle in prion disease, which can behave like an infectious organism but does not appear to depend on nucleic acid. Lipid vesicles or rafts may resemble endosomes, which would be consistent with reports of prion being transported and formed along an endosome--like pathway. Additionally, the vesicles or rafts could accumulate intra--cellularly, and might form tubulovesicular structures, which are hallmarks of prion disease. Potential applications of this theory to more common protein misfolding diseases, Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, are discussed. This theory, which I term the mineral--lipid prion hypothesis, provides a basis for potential novel interventions in the field of prion and protein--misfolding diseases. In addition, this theory suggests that similar silicate--or mineral--catalyzed lipid vesicles/liposomes might be further explored as useful compartments that could be manipulated in order to deliver molecules or even proteins to or from cells.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2982v1 | CC BY 4.0

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Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Hackl

Becker

2019

Journal of Peptide Science

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Deciphering the pathophysiologic events in prion diseases is challenging, and the role of posttranslational modifications (PTMs) such as glypidation and glycosylation remains elusive due to the lack of homogeneous protein preparations. So far, experimental studies have been limited in directly analyzing the earliest events of the conformational change of cellular prion protein (PrPC) into scrapie prion protein (PrPSc) that further propagates PrPC misfolding and aggregation at the cellular membrane, the initial site of prion infection, and PrP misfolding, by a lack of suitably modified PrP variants. PTMs of PrP, especially attachment of the glycosylphosphatidylinositol (GPI) anchor, have been shown to be crucially involved in the PrPSc formation. To this end, semisynthesis offers a unique possibility to understand PrP behavior in vitro and in vivo as it provides access to defined site‐selectively modified PrP variants. This approach relies on the production and chemoselective linkage of peptide segments, amenable to chemical modifications, with recombinantly produced protein segments. In this article, advances in understanding PrP conversion using semisynthesis as a tool to obtain homogeneous posttranslationally modified PrP will be discussed.

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Visualization of Prion Infection in Transgenic Mice Expressing Green Fluorescent Protein-Tagged Prion Protein

Cited by 46 publications

References 40 publications

Prions disturb post-Golgi trafficking of membrane proteins

Prions disturb post-Golgi trafficking of membrane proteins

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

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