scholarly journals Effect of Glycans and the Glycophosphatidylinositol Anchor on Strain Dependent Conformations of Scrapie Prion Protein: Improved Purifications and Infrared Spectra

Biochemistry ◽  
2011 ◽  
Vol 50 (21) ◽  
pp. 4479-4490 ◽  
Author(s):  
Gerald S. Baron ◽  
Andrew G. Hughson ◽  
Gregory J. Raymond ◽  
Danielle K. Offerdahl ◽  
Kelly A. Barton ◽  
...  
Keyword(s):  
Prion Protein ◽  
Infrared Spectra ◽  
Strain Dependent ◽  
Glycophosphatidylinositol Anchor

scholarly journals Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

2020 ◽  
Vol 21 (19) ◽  
pp. 7260
Author(s):  
Keiji Uchiyama ◽  
Hironori Miyata ◽  
Yoshitaka Yamaguchi ◽  
Morikazu Imamura ◽  
Mariya Okazaki ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Prion Infection ◽  
Amplification Assay ◽  
The Brain ◽  
Strain Dependent

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

scholarly journals Strain-dependent profile of misfolded prion protein aggregates

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Rodrigo Morales ◽  
Ping Ping Hu ◽  
Claudia Duran-Aniotz ◽  
Fabio Moda ◽  
Rodrigo Diaz-Espinoza ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Aggregates ◽  
Strain Dependent

scholarly journals Prion Strain-Dependent Differences in Conversion of Mutant Prion Proteins in Cell Culture

2006 ◽  
Vol 80 (16) ◽  
pp. 7854-7862 ◽  
Author(s):  
Ryuichiro Atarashi ◽  
Valerie L. Sim ◽  
Noriyuki Nishida ◽  
Byron Caughey ◽  
Shigeru Katamine
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Basic Amino Acid ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Prion Strain ◽  
Potent Inhibitory Effect ◽  
Scrapie Strain ◽  
Infected Cells ◽  
Strain Dependent

ABSTRACT Although the protein-only hypothesis proposes that it is the conformation of abnormal prion protein (PrPSc) that determines strain diversity, the molecular basis of strains remains to be elucidated. In the present study, we generated a series of mutations in the normal prion protein (PrPC) in which a single glutamine residue was replaced with a basic amino acid and compared their abilities to convert to PrPSc in cultured neuronal N2a58 cells infected with either the Chandler or 22L mouse-adapted scrapie strain. In mice, these strains generate PrPSc of the same sequence but different conformations, as judged by infrared spectroscopy. Substitutions at codons 97, 167, 171, and 216 generated PrPC that resisted conversion and inhibited the conversion of coexpressed wild-type PrP in both Chandler-infected and 22L-infected cells. Interestingly, substitutions at codons 185 and 218 gave strain-dependent effects. The Q185R and Q185K PrP were efficiently converted to PrPSc in Chandler-infected but not 22L-infected cells. Conversely, Q218R and Q218H PrP were converted only in 22L-infected cells. Moreover, the Q218K PrP exerted a potent inhibitory effect on the conversion of coexpressed wild-type PrP in Chandler-infected cells but had little effect on 22L-infected cells. These results show that two strains with the same PrP sequence but different conformations have differing abilities to convert the same mutated PrPC.

scholarly journals The role of glycophosphatidylinositol anchor in the amplification of the scrapie isoform of prion protein in vitro

FEBS Letters ◽  
2009 ◽  
Vol 583 (22) ◽  
pp. 3671-3675 ◽  
Author(s):  
Jae-Il Kim ◽  
Krystyna Surewicz ◽  
Pierluigi Gambetti ◽  
Witold K. Surewicz
Keyword(s):  
Prion Protein ◽  
Glycophosphatidylinositol Anchor

scholarly journals Strain-Dependent Effect of Macroautophagy on Abnormally Folded Prion Protein Degradation in Infected Neuronal Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0137958 ◽  
Author(s):  
Daisuke Ishibashi ◽  
Takujiro Homma ◽  
Takehiro Nakagaki ◽  
Takayuki Fuse ◽  
Kazunori Sano ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Prion Protein ◽  
Neuronal Cells ◽  
Dependent Effect ◽  
Strain Dependent

scholarly journals Orally Administered Amyloidophilic Compound Is Effective in Prolonging the Incubation Periods of Animals Cerebrally Infected with Prion Diseases in a Prion Strain-Dependent Manner

2007 ◽  
Vol 81 (23) ◽  
pp. 12889-12898 ◽  
Author(s):  
Yuri Kawasaki ◽  
Keiichi Kawagoe ◽  
Chun-jen Chen ◽  
Kenta Teruya ◽  
Yuji Sakasegawa ◽  
...  
Keyword(s):  
Prion Protein ◽  
Therapeutic Efficacy ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Therapeutic Interventions ◽  
Dependent Manner ◽  
Cell Culture Study ◽  
Prion Strain ◽  
Incubation Periods ◽  
Strain Dependent

ABSTRACT The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain-dependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that diglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.

scholarly journals Strain-dependent Differences in β-Sheet Conformations of Abnormal Prion Protein

1998 ◽  
Vol 273 (48) ◽  
pp. 32230-32235 ◽  
Author(s):  
Byron Caughey ◽  
Gregory J. Raymond ◽  
Richard A. Bessen
Keyword(s):  
Prion Protein ◽  
Β Sheet ◽  
Strain Dependent

scholarly journals The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

2010 ◽  
Vol 6 (4) ◽  
pp. e1000859 ◽  
Author(s):  
Philippe Tixador ◽  
Laëtitia Herzog ◽  
Fabienne Reine ◽  
Emilie Jaumain ◽  
Jérôme Chapuis ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Aggregates ◽  
Physical Relationship ◽  
Strain Dependent ◽  
Is Strain

scholarly journals Expression of unglycosylated mutated prion protein facilitates PrPSc formation in neuroblastoma cells infected with different prion strains

2000 ◽  
Vol 81 (10) ◽  
pp. 2555-2563 ◽  
Author(s):  
Carsten Korth ◽  
Kiyotoshi Kaneko ◽  
Stanley B. Prusiner
Keyword(s):  
Plasma Membrane ◽  
Steady State ◽  
Transgenic Mice ◽  
Prion Protein ◽  
Neuroblastoma Cells ◽  
Prion Strains ◽  
Mouse Neuroblastoma ◽  
Steady State Levels ◽  
Different Strains ◽  
Glycophosphatidylinositol Anchor

Prion replication involves conversion of the normal, host-encoded prion protein PrPC, which is a sialoglycoprotein bound to the plasma membrane by a glycophosphatidylinositol anchor, into a pathogenic isoform, PrPSc. In earlier studies, tunicamycin prevented glycosylation of PrPC in scrapie-infected mouse neuroblastoma (ScN2a) cells but it was still expressed on the cell surface and converted into PrPSc; mutation of PrPC at glycosylation consensus sites (T182A, T198A) produced low steady-state levels of PrP that were insufficient to propagate prions in transgenic mice. By mutating asparagines to glutamines at the consensus sites, we obtained expression of unglycosylated, epitope-tagged MHM2PrP(N180Q,N196Q), which was converted into PrPSc in ScN2a cells. Cultures of uninfected neuroblastoma (N2a) cells transiently expressing mutated PrP were exposed to brain homogenates prepared from mice infected with the RML, Me7 or 301V prion strains. In each case, mutated PrP was converted into PrPSc as judged by Western blotting. These findings raise the possibility that the N2a cell line can support replication of different strains of prions.

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