Chemical and biophysical insights into the propagation of prion strains

Falsig, Jeppe; Nilsson, K. Peter R.; Knowles, Tuomas P. J.; Aguzzi, Adriano

doi:10.2976/1.2990786

Cited by 30 publications

(20 citation statements)

References 102 publications

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“…Such preservation of prion strain characteristics through passage on deletion mutant PrPs is in line with the prion ability to propagate onto a new PrP sequence while retaining its strain-specific properties in some cases of interspecies transmission (64). The specificity of prion strains is thought to rely on more or less subtle 3D and/or 4D structural differences (65,66), suggesting that deletions 193-196 and 193-197 have few, if any impact on prion structure. What do these findings bring to our knowledge in the context of the proposed PrP Sc structural models?…”

Section: Discussionmentioning

confidence: 88%

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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Section: Discussionmentioning

confidence: 88%

Generating Bona Fide Mammalian Prions with Internal Deletions

Muñoz-Montesino

Sizun

Moudjou

et al. 2016

J Virol

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“…Such "strain" properties in animal TSEs, for example scrapie, BSE, chronic wasting disease, as well as in human TSE, for example variant CJD, have been well documented. 22 Nevertheless, the presence of type-I PrP Sc in the brain tissues of this case clearly influence the electrophoretic patterns of the total PrP in Western blots, with predominant monoglycosyl signals of total PrP in the PrP Sc -positive regions and predominant diglycosyl ones in the PrP Sc negative regions, which reflect a common phenomenon in human and animal TSEs. 23 Previous studies have showed that the PrP Sc molecules in one infected tissue present diversity in their N-terminus after proteolysis, although the cleavage site of proteinase on PrP Sc restricts to a narrow region.…”

Section: Discussionmentioning

confidence: 93%

The diversities of PrP^Sc distributions and pathologic changes in various brain regions from a Chinese patient with G114V genetic CJD

et al. 2011

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Human genetic Creutzfeldt-Jakob disease (gCJD; one of the prion diseases) is caused by point mutations and insertions in the prion protein gene (PRNP). Previously we have reported a Chinese gCJD case with a substitution of valine (V) for glycine (G) at codon 114. To investigate the detailed pathogenic and pathologic characteristics of G114V gCJD, 10 different brain regions were thoroughly analyzed. PrP-specific Western blots and immunohistochemical (IHC) assays identified larger amounts of PrP(Sc) in the regions of brain cortex. Assays of the transcriptions of PrP-specific mRNA by RT-PCR and real-time PCR showed comparable levels in 10 brain regions. In line with the distribution of PrP(Sc) , typical vacuolations in brains, markedly in four cortex regions, were detected. Contrast to the distributing features of spongiform and of PrP(Sc) , massive gliosis was detected in all brain regions by GFAP-specific IHC tests. Moreover, two-dimensional gel immunoblots found three major sets of PrP(Sc) spots, indicating that PrP(Sc) in brain tissues was a mixture of molecules with different biochemical properties. The data here provide the pathogenic and neuropathological features of G114V gCJD.

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“…This structure–activity relationship 5,45 is, however, very difficult to verify at equilibrium due to the transient nature of the metastable species populated during fibril formation 7,46,47 . Establishing structure–activity relationships in amyloid structures is also important because the phenotypic traits associated with prion diseases are due to the existence of different amyloid morphologies, formed by the same sequence and presenting different physical and structural properties, the so-called prion strains 14 . The availability of kinetically stable amyloid morphologies of lysozyme with different degrees of cross-β structure, which can be formed under controlled and reproducible conditions, has given us a unique opportunity to determine whether the presence of large non-core regions in the fibrillar material is related to cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity

Mossuto

Dhulesia

Devlin

et al. 2010

Journal of Molecular Biology

100

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Identifying the cause of the cytotoxicity of species populated during amyloid formation is crucial to understand the molecular basis of protein deposition diseases. We have examined different types of aggregates formed by lysozyme, a protein found as fibrillar deposits in patients with familial systemic amyloidosis, by infrared spectroscopy, transmission electron microscopy, and depolymerization experiments, and analyzed how they affect cell viability. We have characterized two types of human lysozyme amyloid structures formed in vitro that differ in morphology, molecular structure, stability, and size of the cross-β core. Of particular interest is that the fibrils with a smaller core generate a significant cytotoxic effect. These findings indicate that protein aggregation can give rise to species with different degree of cytotoxicity due to intrinsic differences in their physicochemical properties.

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Chemical and biophysical insights into the propagation of prion strains

Cited by 30 publications

References 102 publications

Generating Bona Fide Mammalian Prions with Internal Deletions

Generating Bona Fide Mammalian Prions with Internal Deletions

The diversities of PrP^Sc distributions and pathologic changes in various brain regions from a Chinese patient with G114V genetic CJD

The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity

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Chemical and biophysical insights into the propagation of prion strains

Cited by 30 publications

References 102 publications

Generating Bona Fide Mammalian Prions with Internal Deletions

Generating Bona Fide Mammalian Prions with Internal Deletions

The diversities of PrPSc distributions and pathologic changes in various brain regions from a Chinese patient with G114V genetic CJD

The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity

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The diversities of PrP^Sc distributions and pathologic changes in various brain regions from a Chinese patient with G114V genetic CJD