Evaluating Prion Models Based on Comprehensive Mutation Data of Mouse PrP

Shirai, Tomoyuki; Saito, Michio; Kobayashi, Atsushi; Asano, Masahiro; Hizume, Masaki; Ikeda, Shino; Teruya, Kenta; Morita, Masanori; Kitamoto, Tetsuyuki

doi:10.1016/j.str.2013.12.019

Cited by 22 publications

(30 citation statements)

References 66 publications

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“…Recent studies, including ours, showed that prion conversion tolerates a certain level of sequence changes at the junction of PrP helices H2 and H3, suggesting that this region might be less essential (10,(34)(35)(36)(37). We show here that a deletion of a stretch of residues forming the C terminus of helix H2 of PrP C is plainly compatible with prion conversion and transfer of strain properties.…”

supporting

confidence: 52%

“…We propose instead that the 193-197 area, which is alpha-helical in PrP C , is converted into an element that might be less critical for PrP Sc structure, i.e., an unstructured loop segment. This is also supported by different observations: the region tolerates insertion of unrelated heptapeptide or octapeptide (34,36) or replacement of one of the four threonines by a cysteine (10) and also individual replacement of each amino acids by any other one (37); this region is also significantly more accessible to deuterium exchange than surrounding areas (4); and, finally, in the particular example of the HETs prion of Podospora anserina whose structure is resolved, a series of short deletions was performed, and the only ones compatible with prion conversion were found to localize in the loop connecting the two stacked rings of beta strands forming the amyloid fiber (67). Therefore, our results are incompatible with PrP Sc models including residues 193 to 197 into a beta strand (11,68).…”

Section: Discussionmentioning

confidence: 59%

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Generating Bona Fide Mammalian Prions with Internal Deletions

Muñoz-Montesino

Sizun

Moudjou

et al. 2016

J Virol

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Mammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions. IMPORTANCEPrions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.

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supporting

confidence: 52%

Section: Discussionmentioning

confidence: 59%

Generating Bona Fide Mammalian Prions with Internal Deletions

Muñoz-Montesino

Sizun

Moudjou

et al. 2016

J Virol

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“…One fibril model of the HET-s peptide (37) and insulin (32) and two models of PrP fibrils (38,39) were stretched along the fibril axis, which allows determination of the modulus and strength from stress-strain curves (Figs. 3 A and S11 A).…”

Section: Correlation Between Nanomechanics and H-bond Densitiesmentioning

confidence: 99%

Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Lamour

Nassar

Chan

et al. 2017

Biophysical Journal

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Amyloids are fibrillar nanostructures of proteins that are assembled in several physiological processes in human cells (e.g., hormone storage) but also during the course of infectious (prion) and noninfectious (nonprion) diseases such as Creutzfeldt-Jakob and Alzheimer's diseases, respectively. How the amyloid state, a state accessible to all proteins and peptides, can be exploited for functional purposes but also have detrimental effects remains to be determined. Here, we measure the nanomechanical properties of different amyloids and link them to features found in their structure models. Specifically, we use shape fluctuation analysis and sonication-induced scission in combination with full-atom molecular dynamics simulations to reveal that the amyloid fibrils of the mammalian prion protein PrP are mechanically unstable, most likely due to a very low hydrogen bond density in the fibril structure. Interestingly, amyloid fibrils formed by HET-s, a fungal protein that can confer functional prion behavior, have a much higher Young's modulus and tensile strength than those of PrP, i.e., they are much stiffer and stronger due to a tighter packing in the fibril structure. By contrast, amyloids of the proteins RIP1/RIP3 that have been shown to be of functional use in human cells are significantly stiffer than PrP fibrils but have comparable tensile strength. Our study demonstrates that amyloids are biomaterials with a broad range of nanomechanical properties, and we provide further support for the strong link between nanomechanics and b-sheet characteristics in the amyloid core.

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“…Currently, there are no curative treatments for AD and other prion diseases, and also the underlying mechanism had not been fully elucidated (Karamanos et al, 2015, Visanji et al, 2013, Wisniewski and Drummond, 2016. On the other hand, there were no appropriate animal models or limited animal models for the drug development research (Fernandez-Borges et al, 2013, Ghate et al, 2014, Shirai et al, 2014. In the last 20 years, several mouse models had been established and were used in a number of research fields of prion diseases, including pathology (Corda et al, 2015, Ghate et al, 2014 and genetics (Asante et al, 2015, Friedman-Levi et al, 2011.…”

Section: Prnp Polymorphisms In Six Mouse Strainsmentioning

confidence: 99%

“…An important limitation was the existence of appropriate models of the disease (Fernandez-Borges et al, 2013). In order to study the molecular mechanism of the prion diseases and to test the drugs, many mouse models had been established and they are required (Asante et al, 2015, Bajsarowicz et al, 2012, Bruce et al, 2002, FernandezBorges et al, 2015, Friedman-Levi et al, 2011, Lee et al, 2013, Morales et al, 2015, Shirai et al, 2014. Among these mouse models, there included a number of transgenic models which are expensive, with short life, clinical symptoms and genetic instability, and other associated problems.…”

Section: Prnp Polymorphisms In Six Mouse Strainsmentioning

confidence: 99%

Analysis of experimental mouse PRNP genetic polymorphisms and their susceptibility to prion diseases

Gao

Cai

et al. 2017

IJAR

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Research studies showed that the polymorphisms in prion protein gene (PRNP) were associated with susceptibility to prion diseases in several animals, including humans and mouse. Several mouse strains carried natural PRNP mutations which had been identified and these could provide as animal models for human prion diseases. In this study, the genetic polymorphisms of PRNP in six common mouse strains were investigated. The experimental mice included KM mouse, ICR mouse, DBA mouse, C3H/He mouse, C57BL mouse and BALB mouse. The results showed only one new polymorphism was identified compared with the reference sequence. The identified new mutation site was C564T and it was homozygous, but this locus did not result in amino acid change. Sequence analyses suggested that these six mouse strains were susceptible to prion diseases and are suitable as susceptibility models of prion diseases.

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Evaluating Prion Models Based on Comprehensive Mutation Data of Mouse PrP

Cited by 22 publications

References 66 publications

Generating Bona Fide Mammalian Prions with Internal Deletions

Generating Bona Fide Mammalian Prions with Internal Deletions

Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Analysis of experimental mouse PRNP genetic polymorphisms and their susceptibility to prion diseases

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