Selective Neuronal Targeting in Prion Disease

DeArmond, Stephen J.; Sánchez, Henry; Yehiely, Fruma; Qiu, Yin Long; Ninchak-Casey, Anne; Daggett, Valerie; Camerino, A. P.; Cayetano, Juliana; Rogers, Mark; Groth, Darlene; Torchia, Marilyn; Tremblay, Patrick; Scott, Michael; Cohen, Fred E.; Prusiner, Stanley B.

doi:10.1016/s0896-6273(00)80424-9

Cited by 196 publications

(167 citation statements)

References 79 publications

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“…7, B and C), suggesting that the presence of just one sugar chain at either the first or the second site is sufficient for its trafficking through the secretory pathway to the external membrane. This differs from previous reports in transgenic mice overexpressing monoglycosylated hamster PrP or in transfected cell cultures, where altering the first glycosylation consensus site influenced the intracellular fate of PrP, blocking its trafficking to the cell membrane (16,21,49).…”

Section: Unglycosylated Prp Localization Is Mainly Intracellular Whecontrasting

confidence: 99%

“…This discrepancy of results obtained may be the result of a combination of factors: different point mutations introduced in the PrP gene, different constructs, distinct cell lines, random integration of the transgene, and different levels of Prnp expression or in some cases use of drugs to prevent glycosylation that can cause intracellular stress. Moreover, experiments that introduced the T182A mutation to abolish the attachment of sugars at the first site (16,20,21) may be misleading, since this mutated PrP can cause familial TSE disease (49,53) in a glycosylationindependent manner (54).…”

Section: Discussionmentioning

confidence: 99%

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Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Cancellotti

Wiseman

Tuzi

et al. 2005

Journal of Biological Chemistry

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N-Linked glycans have been shown to have an important role in the cell biology of a variety of cell surface glycoproteins, including PrP protein. It has been suggested that glycosylation of PrP can influence the susceptibility to transmissible spongiform encephalopathy and determine the characteristics of the many different strains observed in this particular type of disease. To understand the role of carbohydrates in influencing the PrP maturation, stability, and cell biology, we have produced and analyzed gene-targeted murine models expressing differentially glycosylated PrP. Transgenic mice carrying the PrP substitution threonine for asparagine 180 (G1) or threonine for asparagine 196 (G2) or both mutations combined (G3), which eliminate the first, second, and both glycosylation sites, respectively, have been generated by double replacement gene targeting. An in vivo analysis of altered PrP has been carried out in transgenic mouse brains, and our data show that the lack of glycans does not influence PrP maturation and stability. The presence of one chain of sugar is sufficient for the trafficking to the cell membrane, whereas the unglycosylated PrP localization is mainly intracellular. However, this altered cellular localization of PrP does not lead to any overt phenotype in the G3 transgenic mice. Most importantly, we found that, in vivo, unglycosylated PrP does not acquire the characteristics of the aberrant pathogenic form (PrP Sc ), as was previously reported using in vitro models.

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Section: Unglycosylated Prp Localization Is Mainly Intracellular Whecontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Cancellotti

Wiseman

Tuzi

et al. 2005

Journal of Biological Chemistry

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“…A possible relation of strain-specific glycoform distribution with the neuroanatomical targeting of infection has been considered (21,49), but conflicting results were discussed regarding some possible differences of PrP res glycoform ratios between different neuroanatomical regions in a single TSE-infected host (35,49). The distribution of abnormal PrP in our ovine transgenic mice is presently being studied, but it should be noticed that these mice express the sheep prion protein under the control of the neuron-specific enolase promoter, which may strongly influence the features of PrP C expression.…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

Baron¹,

Crozet²,

Biacabe³

et al. 2004

J Virol

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The existence of different strains of infectious agents involved in scrapie, a transmissible spongiform encephalopathy (TSE) of sheep and goats, remains poorly explained. These strains can, however, be differentiated by characteristics of the disease in mice and also by the molecular features of the protease-resistant prion protein (PrP res ) that accumulates into the infected tissues. For further analysis, we first transmitted the disease from brain samples of TSE-infected sheep to ovine transgenic [Tg(OvPrP4)] and to wild-type (C57BL/6) mice. We show that, as in sheep, molecular differences of PrP res detected by Western blotting can differentiate, in both ovine transgenic and wild-type mice, infection by the bovine spongiform encephalopathy (BSE) agent from most scrapie sources. Similarities of an experimental scrapie isolate (CH1641) with BSE were also likewise found following transmission in ovine transgenic mice. Secondly, we transmitted the disease to ovine transgenic mice by inoculation of brain samples of wild-type mice infected with different experimental scrapie strains (C506M3, 87V, 79A, and Chandler) or with BSE. Features of these strains in ovine transgenic mice were reminiscent of those previously described for wild-type mice, by both ratios and by molecular masses of the different PrP res glycoforms. Moreover, these studies revealed the diversity of scrapie strains and their differences with BSE according to labeling by a monoclonal antibody (P4). These data, in an experimental model expressing the prion protein of the host of natural scrapie, further suggest a genuine diversity of TSE infectious agents and emphasize its linkage to the molecular features of the abnormal prion protein.

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“…The question arises of whether the spectrum of PrP Sc conformations allowed by PrP C might differ to a certain extent among the tissues or brain regions. PrP C isoforms or glycoforms exhibit a regional heterogeneity in the brain [19,63,64]. It is tempting to suggest that this might modulate the capacity of a prion to cross the species barrier.…”

mentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Selective Neuronal Targeting in Prion Disease

Cited by 196 publications

References 79 publications

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

Prion agent diversity and species barrier

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