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[PMID]: 29458424
[Au] Autor:Race B; Williams K; Hughson AG; Jansen C; Parchi P; Rozemuller AJM; Chesebro B
[Ad] Address:Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT, 59840, USA. raceb@nih.gov.
[Ti] Title:Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein.
[So] Source:Acta Neuropathol Commun;6(1):13, 2018 02 20.
[Is] ISSN:2051-5960
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Human familial prion diseases are associated with mutations at 34 different prion protein (PrP) amino acid residues. However, it is unclear whether infectious prions are found in all cases. Mutant PrP itself may be neurotoxic, or alternatively, PrP mutation might predispose to spontaneous formation of infectious PrP isoforms. Previous reports demonstrated transmission to animal models by human brain tissue expressing 7 different PrP mutations, but 3 other mutations were not transmissible. In the present work, we tested transmission using brain homogenates from patients expressing 3 untested PrP mutants: G131V, Y226X, and Q227X. Human brain homogenates were injected intracerebrally into tg66 transgenic mice overexpressing human PrP. Mice were followed for nearly 800 days.From 593 to 762 dpi, 4 of 8 mice injected with Y226X brain had PrPSc detectable in brain by immunostaining, immunoblot, and PrP amyloid seeding activity assayed by RT-QuIC. From 531 to 784 dpi, 11 of 11 G131V-injected mice had PrPSc deposition in brain, but none were positive by immunoblot or RT-QuIC assay. In contrast, from 529 to 798 dpi, no tg66 mice injected with Q227X brain had PrPSc or PrP amyloid seeding activity detectable by these methods. Y226X is the only one of 4 known PrP truncations associated with familial disease which has been shown to be transmissible. This transmission of prion infectivity from a patient expressing truncated human PrP may have implications for the spread and possible transmission of other aggregated truncated proteins in prion-like diseases such as Alzheimer's disease, Parkinson's disease and tauopathies.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1802
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Process
[do] DOI:10.1186/s40478-018-0516-2

  2 / 2910 MEDLINE  
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[PMID]: 28449707
[Au] Autor:Llorens F; Thüne K; Sikorska B; Schmitz M; Tahir W; Fernández-Borges N; Cramm M; Gotzmann N; Carmona M; Streichenberger N; Michel U; Zafar S; Schuetz AL; Rajput A; Andréoletti O; Bonn S; Fischer A; Liberski PP; Torres JM; Ferrer I; Zerr I
[Ad] Address:Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE), Robert Koch Strasse 40, 37075, Göttingen, Germany. franc.llorens@gmail.com.
[Ti] Title:Altered Ca homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.
[So] Source:Acta Neuropathol Commun;5(1):35, 2017 04 27.
[Is] ISSN:2051-5960
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP ). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca ) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca responsive genes in sCJD brain tissue, accompanied by two Ca -dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
[Mh] MeSH terms primary: Brain/metabolism
Calcium/metabolism
Calpain/metabolism
Cathepsins/metabolism
Creutzfeldt-Jakob Syndrome/metabolism
Homeostasis/physiology
[Mh] MeSH terms secundary: Animals
Brain/pathology
Cations, Divalent/metabolism
Cells, Cultured
Creutzfeldt-Jakob Syndrome/pathology
Disease Models, Animal
Humans
Lysosomes/metabolism
Lysosomes/pathology
Mesocricetus
Mice, Transgenic
Neurons/metabolism
Neurons/pathology
PrPSc Proteins/metabolism
Rats, Wistar
Recombinant Proteins/metabolism
Sheep
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Cations, Divalent); 0 (PrPSc Proteins); 0 (Recombinant Proteins); EC 3.4.- (Cathepsins); EC 3.4.22.- (Calpain); SY7Q814VUP (Calcium)
[Em] Entry month:1712
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[Js] Journal subset:IM
[Da] Date of entry for processing:170429
[St] Status:MEDLINE
[do] DOI:10.1186/s40478-017-0431-y

  3 / 2910 MEDLINE  
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[PMID]: 29220360
[Au] Autor:Eigenbrod S; Frick P; Bertsch U; Mitteregger-Kretzschmar G; Mielke J; Maringer M; Piening N; Hepp A; Daude N; Windl O; Levin J; Giese A; Sakthivelu V; Tatzelt J; Kretzschmar H; Westaway D
[Ad] Address:Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany.
[Ti] Title:Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice.
[So] Source:PLoS One;12(12):e0188989, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, "TetraH>G" allele) or at site 5 (composed of residues His-95 and His-110; "H95G" allele) and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G) at levels comparable to wild-type (wt) controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G) mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G) mice and diffuse PrPSc deposition in (TgPrP(H95G) mice), were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain.
[Mh] MeSH terms primary: Histidine/chemistry
Prion Proteins/chemistry
Scrapie/pathology
[Mh] MeSH terms secundary: Animals
Mice
Mice, Transgenic
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Prion Proteins); 4QD397987E (Histidine)
[Em] Entry month:1801
[Cu] Class update date: 180104
[Lr] Last revision date:180104
[Js] Journal subset:IM
[Da] Date of entry for processing:171209
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188989

  4 / 2910 MEDLINE  
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[PMID]: 29110766
[Au] Autor:Zerr I; Zafar S; Schmitz M; Llorens F
[Ad] Address:Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Göttingen, Göttingen, Germany. Electronic address: ingazerr@med.uni-goettingen.de.
[Ti] Title:Cerebrospinal fluid in Creutzfeldt-Jakob disease.
[So] Source:Handb Clin Neurol;146:115-124, 2017.
[Is] ISSN:0072-9752
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Cerebrospinal fluid (CSF) contains a dynamic and complex mixture of proteins, which reflects physiologic or pathologic states of the central nervous system. Changes in CSF proteome have been described in various neurodegenerative disorders. Earliest publications came from the field of prion disease. Two major approaches have been followed aiming to detect the pathologic form of prion protein (PrPSc) in various peripheral tissues on one hand, but also looking for surrogate parameters as a consequence of the underlying neurodegenerative process. First observations were made using two-dimensional gel electrophoresis for proteins named p130/131, identified as belonging to the 14-3-3 protein family group. This protein became known as the first "wet" biomarker part of clinical diagnostic criteria. Other proteins were identified; most of the work in addition to 14-3-3 has been done on tau/p-tau. The development of PrPSc-based biomarkers was hampered by technical problems and detection limits. A novel technique which uses an amplification procedure followed by an aggregation step (real-time quaking-induced conversion: RT-QuIC) emerged and allows the detection of abnormally folded PrPSc in the CSF. This chapter summarizes the current knowledge of biomarker development in prion disease and discusses perspectives for new approaches.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171107
[Lr] Last revision date:171107
[St] Status:In-Process

  5 / 2910 MEDLINE  
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[PMID]: 28992347
[Au] Autor:Shigemitsu Y; Hiroaki H
[Ad] Address:Laboratory of Structural and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Aichi 464-8601, Japan.
[Ti] Title:Common molecular pathogenesis of disease-related intrinsically disordered proteins revealed by NMR analysis.
[So] Source:J Biochem;, 2017 Sep 11.
[Is] ISSN:1756-2651
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Intrinsically disordered proteins (IDPs) are either completely unstructured or contain large disordered regions in their native state; they have drawn much attention in the field of molecular pathology. Some of them substantially tend to form protein self-assemblies, such as toxic or non-toxic aggregates and fibrils, and have been postulated to relate to diseases. These disease-related IDPs include Aß(1-42) [Alzheimer's disease (AD)], Tau (AD and tauopathy), α-synuclein (Parkinson's disease), and p53 (cancer). Several studies suggest that these aggregation and/or fibril formation processes are often initiated by transient conformational changes of the IDPs prior to protein self-assembly. Interestingly, the pathological molecular processes of these IDPs share multiple common features with those of protein misfolding diseases, such as transmissible spongiform encephalopathy (PrPsc) and AL-amyloidosis (VL-domain of γ-immunoglobulin). This review provides an overview of solution NMR techniques that can help analyze the early and transient events of conformational equilibrium of IDPs and folded proteins.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171009
[Lr] Last revision date:171009
[St] Status:Publisher
[do] DOI:10.1093/jb/mvx056

  6 / 2910 MEDLINE  
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[PMID]: 28922846
[Au] Autor:Honda H; Sasaki K; Takashima H; Mori D; Koyama S; Suzuki SO; Iwaki T
[Ad] Address:Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Higashi-Ku, Fukuoka, Japan; Department of Neurology, Saga-Ken Medical Centre Koseikan, Saga, Japan; Department of Pathology, Saga-Ken Medical Centre Koseikan, Saga, Japan.
[Ti] Title:Different Complicated Brain Pathologies in Monozygotic Twins With Gerstmann-Sträussler-Scheinker Disease.
[So] Source:J Neuropathol Exp Neurol;76(10):854-863, 2017 Oct 01.
[Is] ISSN:1554-6578
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases. The spongiform change and brain atrophy in case 1 were more severe compared with those in case 2. Western-blot analysis identified proteinase-resistant PrP (PrPres) at the molecular weight of 21-30 kDa and 8 kDa in the twins. Gel filtration revealed that PrPres was mainly composed of PrP oligomer. PrPres signal patterns were similar between the twins. Additionally, case 1 showed α-synucleinopathy and case 2 showed Alzheimer disease pathology. These different proteinopathies were involved in the amyloid plaque formations of both cases. The degree of GSS pathology was mainly related to disease duration. The amyloid plaque formations could be decorated by concomitant neuropathological changes such as α-synucleinopathy and tauopathy.
[Mh] MeSH terms primary: Alzheimer Disease/complications
Brain/pathology
Gerstmann-Straussler-Scheinker Disease/complications
Gerstmann-Straussler-Scheinker Disease/pathology
[Mh] MeSH terms secundary: Aged
Autopsy
Brain/metabolism
Female
Gerstmann-Straussler-Scheinker Disease/genetics
Humans
Plaque, Amyloid/etiology
Plaque, Amyloid/pathology
PrPSc Proteins/metabolism
Prion Proteins/metabolism
Synucleins/metabolism
Twins, Monozygotic
[Pt] Publication type:JOURNAL ARTICLE; TWIN STUDY
[Nm] Name of substance:0 (PrPSc Proteins); 0 (Prion Proteins); 0 (Synucleins)
[Em] Entry month:1710
[Cu] Class update date: 171002
[Lr] Last revision date:171002
[Js] Journal subset:IM
[Da] Date of entry for processing:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnen/nlx068

  7 / 2910 MEDLINE  
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[PMID]: 28922400
[Au] Autor:Cieplak AS
[Ad] Address:Department of Chemistry, Bilkent University, Ankara, Turkey.
[Ti] Title:Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions.
[So] Source:PLoS One;12(9):e0180905, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-ß-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer's amyloid ß and tau, Parkinson's α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aß, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions.
[Mh] MeSH terms primary: Electrons
Models, Molecular
Protein Aggregates
Protein Folding
Protein Multimerization
[Mh] MeSH terms secundary: Amyloid beta-Peptides/chemistry
Amyloid beta-Peptides/genetics
Amyloid beta-Peptides/metabolism
Animals
Humans
Hydrogen-Ion Concentration
PrPSc Proteins/chemistry
PrPSc Proteins/genetics
PrPSc Proteins/metabolism
Protein Domains
Protein Stability
Protein Structure, Secondary
alpha-Synuclein/chemistry
alpha-Synuclein/genetics
alpha-Synuclein/metabolism
tau Proteins/chemistry
tau Proteins/genetics
tau Proteins/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Amyloid beta-Peptides); 0 (PrPSc Proteins); 0 (Protein Aggregates); 0 (SNCA protein, human); 0 (alpha-Synuclein); 0 (tau Proteins)
[Em] Entry month:1710
[Cu] Class update date: 171016
[Lr] Last revision date:171016
[Js] Journal subset:IM
[Da] Date of entry for processing:170919
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180905

  8 / 2910 MEDLINE  
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[PMID]: 28910420
[Au] Autor:Groveman BR; Raymond GJ; Campbell KJ; Race B; Raymond LD; Hughson AG; Orrú CD; Kraus A; Phillips K; Caughey B
[Ad] Address:Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
[Ti] Title:Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates.
[So] Source:PLoS Pathog;13(9):e1006623, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant prion protein (rPrP) amyloids prepared without cofactors are non-infectious or much less infectious than bona fide tissue-derived PrPSc. This effect has been associated with differences in folding of the aggregates, manifested in part by reduced solvent exclusion and protease-resistance in rPrP amyloids, especially within residues ~90-160. Substitution of 4 lysines within residues 101-110 of rPrP (central lysine cluster) with alanines (K4A) or asparagines (K4N) allows formation of aggregates with extended proteinase K (PK) resistant cores reminiscent of PrPSc, particularly when seeded with PrPSc. Here we have compared the infectivity of rPrP aggregates made with K4N, K4A or wild-type (WT) rPrP, after seeding with scrapie brain homogenate (ScBH) or normal brain homogenate (NBH). None of these preparations caused clinical disease on first passage into rodents. However, the ScBH-seeded fibrils (only) led to a subclinical pathogenesis as indicated by increases in prion seeding activity, neuropathology, and abnormal PrP in the brain. Seeding activities usually accumulated to much higher levels in animals inoculated with ScBH-seeded fibrils made with the K4N, rather than WT, rPrP molecules. Brain homogenates from subclinical animals induced clinical disease on second passage into "hamsterized" Tg7 mice, with shorter incubation times in animals inoculated with ScBH-seeded K4N rPrP fibrils. On second passage from animals inoculated with ScBH-seeded WT fibrils, we detected an additional PK resistant PrP fragment that was similar to that of bona fide PrPSc. Together these data indicate that both the central lysine cluster and scrapie seeding of rPrP aggregates influence the induction of PrP misfolding, neuropathology and clinical manifestations upon passage in vivo. We confirm that some rPrP aggregates can initiate further aggregation without typical pathogenesis in vivo. We also provide evidence that there is little, if any, biohazard associated with routine RT-QuIC assays.
[Mh] MeSH terms primary: Brain/metabolism
Lysine/metabolism
Prion Proteins/metabolism
Scrapie/metabolism
[Mh] MeSH terms secundary: Amyloid/chemistry
Animals
Brain/pathology
Endopeptidase K/metabolism
Mice, Transgenic
PrPSc Proteins/metabolism
Protein Aggregates/physiology
Recombinant Proteins/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Amyloid); 0 (PrPSc Proteins); 0 (Prion Proteins); 0 (Protein Aggregates); 0 (Recombinant Proteins); EC 3.4.21.64 (Endopeptidase K); K3Z4F929H6 (Lysine)
[Em] Entry month:1710
[Cu] Class update date: 171026
[Lr] Last revision date:171026
[Js] Journal subset:IM
[Da] Date of entry for processing:170915
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006623

  9 / 2910 MEDLINE  
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[PMID]: 28880932
[Au] Autor:Igel-Egalon A; Moudjou M; Martin D; Busley A; Knäpple T; Herzog L; Reine F; Lepejova N; Richard CA; Béringue V; Rezaei H
[Ad] Address:INRA, Université Paris-Saclay, UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France.
[Ti] Title:Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick.
[So] Source:PLoS Pathog;13(9):e1006557, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Mammalian prions, the pathogens that cause transmissible spongiform encephalopathies, propagate by self-perpetuating the structural information stored in the abnormally folded, aggregated conformer (PrPSc) of the host-encoded prion protein (PrPC). To date, no structural model related to prion assembly organization satisfactorily describes how strain-specified structural information is encoded and by which mechanism this information is transferred to PrPC. To achieve progress on this issue, we correlated the PrPSc quaternary structural transition from three distinct prion strains during unfolding and refolding with their templating activity. We reveal the existence of a mesoscopic organization in PrPSc through the packing of a highly stable oligomeric elementary subunit (suPrP), in which the strain structural determinant (SSD) is encoded. Once kinetically trapped, this elementary subunit reversibly loses all replicative information. We demonstrate that acquisition of the templating interface and infectivity requires structural rearrangement of suPrP, in concert with its condensation. The existence of such an elementary brick scales down the SSD support to a small oligomer and provide a basis of reflexion for prion templating process and propagation.
[Mh] MeSH terms primary: PrPC Proteins/metabolism
PrPSc Proteins/metabolism
Prion Diseases/metabolism
Protein Unfolding
[Mh] MeSH terms secundary: Animals
Communicable Diseases
Mice
Protein Conformation
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (PrPC Proteins); 0 (PrPSc Proteins)
[Em] Entry month:1710
[Cu] Class update date: 171017
[Lr] Last revision date:171017
[Js] Journal subset:IM
[Da] Date of entry for processing:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006557

  10 / 2910 MEDLINE  
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[PMID]: 28821618
[Au] Autor:Privat N; Levavasseur E; Yildirim S; Hannaoui S; Brandel JP; Laplanche JL; Béringue V; Seilhean D; Haïk S
[Ad] Address:From the INSERM, UMR S1127, 75013 Paris, France.
[Ti] Title:Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains.
[So] Source:J Biol Chem;292(40):16688-16696, 2017 Oct 06.
[Is] ISSN:1083-351X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrP ). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrP deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease.
[Mh] MeSH terms primary: Brain/metabolism
Creutzfeldt-Jakob Syndrome/metabolism
PrPSc Proteins/metabolism
Protein Folding
Proteostasis Deficiencies/metabolism
[Mh] MeSH terms secundary: Animals
Brain/pathology
Creutzfeldt-Jakob Syndrome/genetics
Creutzfeldt-Jakob Syndrome/pathology
Humans
Mice
Mice, Transgenic
PrPSc Proteins/genetics
Protein Isoforms/genetics
Protein Isoforms/metabolism
Proteostasis Deficiencies/genetics
Proteostasis Deficiencies/pathology
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (PrPSc Proteins); 0 (Protein Isoforms)
[Em] Entry month:1710
[Cu] Class update date: 171011
[Lr] Last revision date:171011
[Js] Journal subset:IM
[Da] Date of entry for processing:170820
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.793646


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