Prions on the move

Weissmann, Charles; Li, Jiali; Mahal, Sukhvir P.; Browning, Shawn

doi:10.1038/embor.2011.192

Cited by 106 publications

(100 citation statements)

References 75 publications

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“…Some investigators have argued for the strain selection mechanism to explain prion mutagenesis (38,39). Our previous studies on serial passage of variant CJD and synthetic prions in Tg mice led to similar conclusions: the selection pressure was for more rapid prion formation, i.e., shorter survival times (9,30,40).…”

Section: Discussionmentioning

confidence: 48%

Drug resistance confounding prion therapeutics

Berry

Lü

Geva

et al. 2013

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

127

202

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Significance As people live longer, the prevalence and economic impact of neurodegenerative diseases rise. No cures or effective treatments exist for any of these fatal disorders, so identifying potential therapeutics that extend survival in animal models is vital. Many neurodegenerative illnesses have been shown to be caused by the accumulation of self-propagating misfolded proteins—the hallmark of prion diseases. We report the efficacy of 2-aminothiazoles, which were identified in cell-based screens as antiprion compounds, in extending the lives of prion-infected animals. Efficacy was limited by the development of drug-resistant prions, which is likely to have important implications for creating therapeutics in many different neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 48%

Drug resistance confounding prion therapeutics

Berry

Lü

Geva

et al. 2013

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

127

202

View full text Add to dashboard Cite

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“…Recent studies show that prion strains are not homogenous but are populated by substrains of prions detectable in vitro. A shift from the main substrain to another may account for a transient change of phenotype of a given strain under particular replication conditions (36). Since our PMCA-generated material could not be directly evaluated in the ECPA, we cannot rule out the possibility that a substrain of RML had been selected in vitro under RNA-depleted conditions and reverted to the original strain upon transmission to mice (23).…”

Section: Discussionmentioning

confidence: 99%

Strain-Specific Role of RNAs in Prion Replication

Saá

Sferrazza

Ottenberg

et al. 2012

J Virol

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Several lines of evidence suggest that various cofactors may be required for prion replication. PrP binds to polyanions, and RNAs were shown to promote the conversion of PrP C into PrP Sc in vitro . In the present study, we investigated strain-specific differences in RNA requirement during in vitro conversion and the potential role of RNA as a strain-specifying component of infectious prions. We found that RNase treatment impairs PrP Sc -converting activity of 9 murine prion strains by protein misfolding cyclic amplification (PMCA) in a strain-specific fashion. While the addition of RNA restored PMCA conversion efficiency, the effect of synthetic polynucleotides or DNA was strain dependent, showing a different promiscuity of prion strains in cofactor utilization. The biological properties of RML propagated by PMCA under RNA-depleted conditions were compared to those of brain-derived and PMCA material generated in the presence of RNA. Inoculation of RNA-depleted RML in Tga20 mice resulted in an increased incidence of a distinctive disease phenotype characterized by forelimb paresis. However, this abnormal phenotype was not conserved in wild-type mice or upon secondary transmission. Immunohistochemical and cell panel assay analyses of mouse brains did not reveal significant differences between mice injected with the different RML inocula. We conclude that replication under RNA-depleted conditions did not modify RML prion strain properties. Our study cannot, however, exclude small variations of RML properties that would explain the abnormal clinical phenotype observed. We hypothesize that RNA molecules may act as catalysts of prion replication and that variable capacities of distinct prion strains to utilize different cofactors may explain strain-specific dependency upon RNA.

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“…This could have produced and propagated homogenous or heterogeneous PrPres conformers that structurally differ (in addition to mere size variations) from their parent seeds. If, in contrast, prion strains existed in their biological hosts as stable ensembles of different self-replicative PrP conformers, as suggested by the "quasispecies" model (9,49), specific PMCA conditions, such as those used in our study, may have favored a non-natural selection of certain PrPres conformers. In this case, our PMCA could have caused the detected structural alterations by changing the composition of the 263K quasispecies in the 263K-PMCA material.…”

Section: Different Resistance Of 263k-brain 263k-pmca and 263k-pmcamentioning

confidence: 99%

Infrared Microspectroscopy Detects Protein Misfolding Cyclic Amplification (PMCA)-induced Conformational Alterations in Hamster Scrapie Progeny Seeds

Daus

Wagenführ

Thomzig

et al. 2013

Journal of Biological Chemistry

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Background: It is currently under discussion whether protein misfolding cyclic amplification (PMCA) alters strain properties of prions. Results: An improved infrared microspectroscopic approach combined with biochemical and bioassay data revealed altered strain properties of hamster 263K scrapie prions due to PMCA. Conclusion: PMCA can alter strain properties of 263K prions. Significance: Our analytical approach may help to improve the understanding of prion strain conversion.

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Prions on the move

Cited by 106 publications

References 75 publications

Drug resistance confounding prion therapeutics

Drug resistance confounding prion therapeutics

Strain-Specific Role of RNAs in Prion Replication

Infrared Microspectroscopy Detects Protein Misfolding Cyclic Amplification (PMCA)-induced Conformational Alterations in Hamster Scrapie Progeny Seeds

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