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14 results on '"Stéphanie Prigent"'

1. An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation.

Author

Stéphanie Prigent, Annabelle Ballesta, Frédérique Charles, Natacha Lenuzza, Pierre Gabriel, Léon Matar Tine, Human Rezaei, and Marie Doumic

Subjects
Medicine, Science
Abstract

Protein polymerization consists in the aggregation of single monomers into polymers that may fragment. Fibrils assembly is a key process in amyloid diseases. Up to now, protein aggregation was commonly mathematically simulated by a polymer size-structured ordinary differential equations (ODE) system, which is infinite by definition and therefore leads to high computational costs. Moreover, this Ordinary Differential Equation-based modeling approach implies biological assumptions that may be difficult to justify in the general case. For example, whereas several ordinary differential equation models use the assumption that polymerization would occur at a constant rate independently of polymer size, it cannot be applied to certain protein aggregation mechanisms. Here, we propose a novel and efficient analytical method, capable of modelling and simulating amyloid aggregation processes. This alternative approach consists of an integro-Partial Differential Equation (PDE) model of coalescence-fragmentation type that was mathematically derived from the infinite differential system by asymptotic analysis. To illustrate the efficiency of our approach, we applied it to aggregation experiments on polyglutamine polymers that are involved in Huntington's disease. Our model demonstrates the existence of a monomeric structural intermediate [Formula: see text] acting as a nucleus and deriving from a non polymerizing monomer ([Formula: see text]). Furthermore, we compared our model to previously published works carried out in different contexts and proved its accuracy to describe other amyloid aggregation processes.

Published
2012
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4. Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein

Author

Vincenzo Granata, Annalisa Pastore, Kris Pauwels, Stéphanie Prigent, Paola Cavaliere, Human Rezaei, Adriana Zagari, Joan Torrent, Dipartimento delle Scienze Biologiche, Università degli studi di Napoli Federico II, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Molecular Structure, The National Institute for Medical Research, Dipartimento di Scienze Biologiche & CNISM, Università degli Studi di Napoli, Cavaliere, Paola, Torrent, Joan, Prigent, Stephanie, Granata, Vincenzo, Pauwels, Kri, Pastore, Annalisa, Rezaei, Human, Zagari, Adriana, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))

Subjects
Protein Conformation, [SDV]Life Sciences [q-bio], MESH: Amino Acid Sequence, Neurodegenerative disease, Oligomer, Mice, chemistry.chemical_compound, MESH: Protein Conformation, 0302 clinical medicine, Protein structure, MESH: Animals, Peptide sequence, 0303 health sciences, MESH: Kinetics, PrP fiber, 3. Good health, Biochemistry, Prion, Molecular Medicine, Protein folding, medicine.symptom, Human, PrP oligomer, Prions, Molecular Sequence Data, MESH: Sheep, Anti-prion agent, Protein–protein interaction, Turn (biochemistry), 03 medical and health sciences, MESH: Prions, Amyloidogenic protein, medicine, Animals, Humans, Amino Acid Sequence, Binding site, Protein Interactions, MESH: Mice, Molecular Biology, 030304 developmental biology, Kinetic, Binding Sites, Sheep, MESH: Humans, MESH: Molecular Sequence Data, Animal, Binding Site, Methylene Blue, Kinetics, MESH: Binding Sites, chemistry, Mechanism of action, Biophysics, 030217 neurology & neurosurgery, MESH: Methylene Blue
Abstract

International audience; Neurodegenerative protein misfolding diseases, including prionopathies, share the common feature of accumulating specific misfolded proteins, with a molecular mechanism closely related. Misfolded prion protein (PrP) generates soluble oligomers that, in turn, aggregate into amyloid fibers. Preventing the formation of these entities, crucially associated with the neurotoxic and/or infectious properties of the resulting abnormal PrP, represents an attractive therapeutic strategy to ameliorate prionopathies. We focused our attention into methylene blue (MB), a well-characterized drug, which is under study against Alzheimer's disease and other neurodegenerative disorders. Here, we have undertaken an in vitro study on the effects of MB on oligomerization and fibrillization of human, ovine and murine PrP. We demonstrated that MB affects the kinetics of PrP oligomerization and reduces the amount of oligomer of about 30%, in a pH-dependent manner, by using SLS and DSC methodologies. Moreover, TEM images showed that MB completely suppresses fiber formation at a PrP:MB molar ratio of 1:2. Finally, NMR revealed a direct interaction between PrP and MB, which was mapped on a surface cleft including a fibrillogenic region of the protein. Our results allowed to surmise a mechanism of action in which the MB binding to PrP surface markedly interferes with the pathway towards oligomers and fibres. Therefore MB could be considered as a general anti-aggregation compound, acting against proteinopathies.

Published
2013
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5. Cross-talk between prion protein and quadruplex-forming nucleic acids: a dynamic complex formation

Author

Human Rezaei, Concetta Giancola, Vincenzo Granata, Stéphanie Prigent, Paola Cavaliere, Bruno Pagano, Adriana Zagari, Università degli studi di Napoli Federico II, CEINGE - Biotecnologie Avanzate, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Cavaliere, PAOLA MARIA GIOVANNA, Pagano, Bruno, Granata, V., Prigent, S., Rezaei, H., Giancola, Concetta, and Zagari, Adriana

Subjects
Gene isoform, Circular dichroism, Prions, [SDV]Life Sciences [q-bio], animal diseases, Biology, Calorimetry, Oligomer, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, heterocyclic compounds, Surface plasmon resonance, Molecular Biology, 030304 developmental biology, 0303 health sciences, Binding Sites, G-quadruplex, Circular Dichroism, RNA, Isothermal titration calorimetry, DNA, Surface Plasmon Resonance, nervous system diseases, G-Quadruplexes, Kinetics, chemistry, Biochemistry, Nucleic acid, prion protein, Thermodynamics, 030217 neurology & neurosurgery, Protein Binding
Abstract

International audience; Prion protein (PrP) is involved in lethal neurodegenerative diseases, and many issues remain unclear about its physio-pathological role. Quadruplex-forming nucleic acids (NAs) have been found to specifically bind to both PrP cellular and pathological isoforms. To clarify the relevance of these interactions, thermodynamic, kinetic and structural studies have been performed, using isothermal titration calorimetry, surface plasmon resonance and circular dichroism methodologies. Three quadruplex-forming sequences, d(TGGGGT), r(GGAGGAGGAGGA), d(GGAGGAGGAGGA), and various forms of PrP were selected for this study. Our results showed that these quadruplexes exhibit a high affinity and specificity toward PrP, with K(D) values within the range 62÷630 nM, and a weaker affinity toward a PrP-β oligomer, which mimics the pathological isoform. We demonstrated that the NA quadruplex architecture is the structural determinant for the recognition by both PrP isoforms. Furthermore, we spotted both PrP N-terminal and C-terminal domains as the binding regions involved in the interaction with DNA/RNAs, using several PrP truncated forms. Interestingly, a reciprocally induced structure loss was observed upon PrP-NA interaction. Our results allowed to surmise a quadruplex unwinding-activity of PrP, that may have a feedback in vivo.

Published
2012
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6. Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Author

Stéphanie Prigent, Zhou Xu, A. Pastore, Franck Mouthon, Miquel Adrover, Jean-Philippe Deslys, Human Rezaei, Emmanuel Comoy, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Molecular Structure, The National Institute for Medical Research, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Xu, Zhou, Adrover, Miquel, Pastore, A, Prigent, Stephanie, Mouthon, Franck, Comoy, Emmanuel, Rezaei, Human, and Deslys, Jean-Philippe

Subjects
Models, Molecular, Protein Folding, PrPSc Proteins, [SDV]Life Sciences [q-bio], animal diseases, Cell, Protein aggregation, Biochemistry, Poly d lysine, Neuroblastoma cell, Mice, chemistry.chemical_compound, 0302 clinical medicine, Polylysine, MESH: , Molecular, 0303 health sciences, 3. Good health, medicine.anatomical_structure, MESH: PrPSc, Protein Binding, Biotechnology, Amyloid, MESH: Protein Folding, Biology, PrP conversion, Aggregation, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Animals, MESH: Protein Binding, Molecular Biology, 030304 developmental biology, Charged polymers, Misfolding, Protein, cell, Virology, MESH: Polylysine, In vitro, Protein Structure, Tertiary, MESH: Cell Line, nervous system diseases, MESH: Protein Structure, chemistry, Biophysics, 030217 neurology & neurosurgery
Abstract

International audience; Misfolding of the prion protein (PrP) is the central feature of prion diseases. The conversion of the normal α-helical PrP(C) into a pathological β-enriched PrP(Sc) constitutes an early event in the infectious process. Several hypotheses, involving different regions of the protein, endeavor to delineate the structural mechanism underlying this change of conformation. All current working hypotheses, however, are based on biophysical and modeling studies, the biological relevance of which still needs to be assessed. We have studied the effect of positively charged polymers on the conversion, using polylysine as a model system, and have investigated a possible mechanism of structural stabilization. We have shown that poly-D-lysine removes proteinase K-resistant PrP from prion-infected SN56 neuroblastoma cells without affecting PrP(C). The effect is enantiospecific since the levorotary isomer, poly-L-lysine, has a markedly weaker effect, likely because of its higher susceptibility to degradation. In vitro cross-linking and NMR studies confirm a direct interaction between polylysine and PrP, which mainly maps to the PrP region containing helices 2 and 3 (H2H3). Interaction prevents conformational conversion and protein aggregation. Our results establish a central role of H2H3 in PrP(Sc) amyloidogenesis and replication and provide biological relevance for the pathological misfolding of this domain.

Published
2011
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7. Information Content in Data Sets for a Nucleated-Polymerization Model

Author

Harvey Thomas Banks, Marie Doumic, Carola Kruse, Stéphanie Prigent, Human Rezaei, Center for Research in Scientific Computation [Raleigh] (CRSC), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Modelling and Analysis for Medical and Biological Applications (MAMBA), Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), MAMBA, European Project: 306321,EC:FP7:ERC,ERC-2012-StG_20111012,SKIPPERAD(2012), and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))

Subjects
FOS: Computer and information sciences, Inverse problems, Amyloid, Protein polymerization, Computer science, Process (engineering), nucleation and growth kinetics, uncertainty quantification, Context (language use), Models, Biological, Sensitivity and Specificity, Statistics - Applications, information content, Article, Polymerization, Computational Engineering, Finance, and Science (cs.CE), Mathematics - Analysis of PDEs, Polyglutamine aggregates, FOS: Mathematics, [MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP], Applications (stat.AP), Sensitivity (control systems), Uncertainty quantification, Computer Science - Computational Engineering, Finance, and Science, protein polymerization, Ecology, Evolution, Behavior and Systematics, Bootstrapping (statistics), [STAT.AP]Statistics [stat]/Applications [stat.AP], Models, Statistical, Ecology, Amyloid fibrils models, Statistical model, [INFO.INFO-NA]Computer Science [cs]/Numerical Analysis [cs.NA], Fisher matrix, Kinetics, Sensitivity Analysis, Content (measure theory), 65M32,62P10,64B10,49Q12, Peptides, Algorithm, Algorithms, Analysis of PDEs (math.AP)
Abstract

We illustrate the use of statistical tools (asymptotic theories of standard error quantification using appropriate statistical models, bootstrapping, and model comparison techniques) in addition to sensitivity analysis that may be employed to determine the information content in data sets. We do this in the context of recent models [S. Prigent, A. Ballesta, F. Charles, N. Lenuzza, P. Gabriel, L.M. Tine, H. Rezaei, and M. Doumic, An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation, PLoS ONE 7 (2012), e43273. doi:10.1371/journal.pone.0043273.] for nucleated polymerization in proteins, about which very little is known regarding the underlying mechanisms; thus, the methodology we develop here may be of great help to experimentalists. We conclude that the investigated data sets will support with reasonable levels of uncertainty only the estimation of the parameters related to the early steps of the aggregation process.

Published
2015
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8. SIZE DISTRIBUTION OF AMYLOID FIBRILS. MATHEMATICAL MODELS AND EXPERIMENTAL DATA

Author

Harvey Thomas Banks, Marie Doumic, Hadjer Wafaa Haffaf, Marc Hoffmann, Human Rezaei, Stéphanie Prigent, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Modelling and Analysis for Medical and Biological Applications (MAMBA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Center for Research in Scientific Computation [Raleigh] (CRSC), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Coalescence (physics), Mathematical model, Chemistry, Depolymerization, Applied Mathematics, General Mathematics, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Nucleation, PrP fiber, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Protein aggregation, Fibril, Becker-Doring system, protein aggregation, Protein filament, Polymerization, Biophysics, statistical test, kernel density estimation
Abstract

International audience; More than twenty types of proteins can adopt misfolded conformations, which can co-aggregate into amyloid fibrils, and are related to pathologies such as Alzheimer's disease. This article surveys mathematical models for aggregation chain reactions, and discuss the ability to use them to understand amyloid distributions. Numerous reactions have been proposed to play a role in their aggregation kinetics, though the relative importance of each reaction in vivo is unclear: these include activation steps, with nucleation compared to initiation, disaggregation steps, with depolymerization compared to fragmentation, and additional processes such as filament coalescence or secondary nucleation. We have statistically analysed the shape of the size distribution of prion fibrils, with the specific example of truncated data due to the experimental technique (electron microscopy). A model of polymerization and depolymerization succeeds in explaining this distribution. It is a very plausible scheme though, as evidenced in the review of other mathematical models, other types of reactions could also give rise to the same type of distributions.

Published
2014
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9. Characterisation of the prion protein oligomerisation by md simulations and small angle X-ray scattering

Author

Cécile A. Dreiss, Stéphanie Prigent, Marc Malfois, Human Rezaei, Nesrine Chakroun, Institute of Pharmaceutical Science, Kings' College London, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), DIAMOND Light source, and Biophysical Society. USA.

Subjects
0303 health sciences, Small-angle X-ray scattering, Brain dysfunction, Low resolution, animal diseases, [SDV]Life Sciences [q-bio], Biophysics, A protein, Biology, Oligomer, nervous system diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Monomer, chemistry, Biochemistry, Prion protein, Large group, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Neurodegenerative diseases constitute a large group of affections characterized by brain dysfunction and degeneration, often occurring with advancing age. Among them, prion diseases are fatal transmissible spongiform encephalopathies (TSEs) affecting Humans (Creutzfeldt-Jacob disease) and animals (BSE or the "Mad cow" disease). The causes of prion diseases have long been debated and it is widely accepted by the scientific community that a protein, namely, the prion protein (PrP), plays a critical role in the disease development. The prion protein or PrP is present in two structurally distinct forms: the natural cellular form (PrPc) and an abnormal polymeric form (PrPsc), which is at the origin of fibrillar deposits found in affected brains. PrPc has been shown to convert into small toxic oligomeric species but the mechanisms of oligomerization are not fully understood. In this study, we have combined Molecular Dynamics (MD) simulations and Small Angle X-ray Scattering (SAXS) to investigate the critical unfolding steps of the ovine prion protein (OvPrP) and to determine the low resolution structure of some of the oligomeric species obtained from various truncated forms of the OvPrP.We show that the domain formed by Helix2 and Helix3 (H2H3) is critical in the unfolding of OvPrP and its conversion of into a beta-rich conformer. The analysis also suggests the incorporation of 9-10 monomer units for all monomeric species studied. We therefore propose that the minimal β-rich core of OvPrP-O3 oligomer is formed by the H2H3 domain while the N-terminal domain either combines with other N-terminal domains to form a second domain or surrounds the oligomeric core.

Published
2014
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10. Decrypting Prion Protein Conversion into a β-Rich Conformer by Molecular Dynamics

Author

Jens Kleinjung, Arianna Fornili, Cécile A. Dreiss, Franca Fraternali, Human Rezaei, Stéphanie Prigent, Nesrine Chakroun, Institute of Pharmaceutical Science, King's College, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), EPSRC/Diamond Light Source (CASE/CNA/07/31) (N.C., C.A.D.), the MRC National Institute for Medical Research (U11758331) (JK) and the Leverhulme Trust (F/07 040/AL) (FF, AF)., and Unité de recherche Virologie et Immunologie Moléculaires (VIM)

Subjects
0303 health sciences, Conformational change, Amyloid, Chemistry, [SDV]Life Sciences [q-bio], Fibril, Article, In vitro, molecular dynamics, Computer Science Applications, prion, 03 medical and health sciences, Crystallography, Molecular dynamics, 0302 clinical medicine, Helix, Biophysics, Hydrogen–deuterium exchange, Physical and Theoretical Chemistry, conversion, Conformational isomerism, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; Prion diseases are fatal neurodegenerative diseases characterized by the formation of β-rich oligomers and the accumulation of amyloid fibrillar deposits in the central nervous system. Understanding the conversion of the cellular prion protein into its β-rich polymeric conformers is fundamental to tackling the early stages of the development of prion diseases. In this paper, we have identified unfolding and refolding steps critical to the conversion into a β-rich conformer for different constructs of the ovine prion protein by molecular dynamics simulations. By combining our results with in vitro experiments, we show that the folded C-terminus of the ovine prion protein is able to recurrently undergo a drastic conformational change by displacement of the H1 helix, uncovering of the H2H3 domain, and formation of persistent β-sheets between H2 and H3 residues. The observed β-sheets refold toward the C-terminus exposing what we call a "bending region" comprising residues 204-214. This is strikingly coincident with the region harboring mutations determining the fate of the prion oligomerization process. The β-rich intermediate is used here for the construction of a putative model for the assembly into an oligomeric aggregate. The results presented here confirm the importance of the H2H3 domain for prion oligomer formation and therefore its potential use as molecular target in the design of novel prion inhibitors.

Published
2013
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11. An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation

Author

Annabelle Ballesta, Stéphanie Prigent, Marie Doumic, Pierre Gabriel, Natacha Lenuzza, Human Rezaei, Frédérique Charles, Léon Matar Tine, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Rythmes Biologiques et Cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nonlinear Analysis for Biology and Geophysical flows (BANG), Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Mathématiques Appliquées aux Systèmes - EA 4037 (MAS), Ecole Centrale Paris, Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mathématiques de Versailles (LMV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), French Agence Nationale de la Recherche, ANR grant [09-BLAN-0218-01], Unité de recherche Virologie et Immunologie Moléculaires (VIM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Université Paris Descartes - Paris 5 (UPD5), Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nonlinear Analysis for Biology and Geophysical flows ( BANG ), Laboratoire Jacques-Louis Lions ( LJLL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Mathématiques Appliquées aux Systèmes - EA 4037 ( MAS ), Artificial Evolution and Computational Biology ( BEAGLE ), Laboratoire d'InfoRmatique en Image et Systèmes d'information ( LIRIS ), Université Lumière - Lyon 2 ( UL2 ) -École Centrale de Lyon ( ECL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université Lumière - Lyon 2 ( UL2 ) -École Centrale de Lyon ( ECL ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Laboratoire de Mathématiques de Versailles ( LMV ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), Doumic, Marie, Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), and Université de Lyon-Université Lumière - Lyon 2 (UL2)

Subjects
Macromolecular Assemblies, Protein polymerization, lcsh:Medicine, Protein aggregation, Bioinformatics, 01 natural sciences, Polymerization, Amyloid disease, [ MATH.MATH-AP ] Mathematics [math]/Analysis of PDEs [math.AP], [MATH.MATH-AP] Mathematics [math]/Analysis of PDEs [math.AP], lcsh:Science, 0303 health sciences, Numerical Analysis, Quantitative Biology::Biomolecules, Multidisciplinary, Partial differential equation, Applied Mathematics, Chemical Reactions, Complex Systems, Neurodegenerative Diseases, Huntington's disease, 010101 applied mathematics, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Chemistry, Neurology, Ordinary differential equation, Medicine, Biological system, Algorithms, Research Article, Protein Binding, Asymptotic analysis, Amyloid, [ SDV.BBM.BP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Differential equation, Biophysics, amyloid diseases, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, 03 medical and health sciences, [MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP], Computer Simulation, 0101 mathematics, Biology, protein polymerization, 030304 developmental biology, lcsh:R, Ode, Models, Theoretical, Kinetics, asymptotic analysis, Nonlinear Dynamics, Computer Science, lcsh:Q, Protein Multimerization, Peptides, Mathematics
Abstract

International audience; Protein polymerization consists in the aggregation of single monomers into polymers that may fragment. Fibrils assembly is a key process in amyloid diseases. Up to now, protein aggregation was commonly mathematically simulated by a polymer size-structured ordinary differential equations (ODE) system, which is infinite by definition and therefore leads to high computational costs. Moreover, this Ordinary Differential Equation-based modeling approach implies biological assumptions that may be difficult to justify in the general case. For example, whereas several ordinary differential equation models use the assumption that polymerization would occur at a constant rate independently of polymer size, it cannot be applied to certain protein aggregation mechanisms. Here, we propose a novel and efficient analytical method, capable of modelling and simulating amyloid aggregation processes. This alternative approach consists of an integro-Partial Differential Equation (PDE) model of coalescence-fragmentation type that was mathematically derived from the infinite differential system by asymptotic analysis. To illustrate the efficiency of our approach, we applied it to aggregation experiments on polyglutamine polymers that are involved in Huntington's disease. Our model demonstrates the existence of a monomeric structural intermediate [Formula: see text] acting as a nucleus and deriving from a non polymerizing monomer ([Formula: see text]). Furthermore, we compared our model to previously published works carried out in different contexts and proved its accuracy to describe other amyloid aggregation processes.

Published
2012
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12. Dual conformation of H2H3 domain of prion protein in mammalian cells

Author

Stéphanie Prigent, Human Rezaei, Jean-Philippe Deslys, Zhou Xu, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and Rezaei, Human

Subjects
Protein Folding, Glycosylation, Glycosylphosphatidylinositols, animal diseases, [SDV]Life Sciences [q-bio], Protein aggregation, Biochemistry, Podospora anserina, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Protein structure, cellule de mammifère, MESH: Animals, 0303 health sciences, biology, MESH: Protein Multimerization, mammifère, MESH: Glycosylation, Cell biology, Protein Structure and Folding, Prion, Protein folding, MESH: Protein aggregation, Rabbits, Amyloid, Prions, MESH: Protein Folding, Protein domain, Context (language use), Protein Chemistry, Cell Line, 03 medical and health sciences, Animals, Benzothiazoles, Molecular Biology, 030304 developmental biology, MESH: Amyloid, Protein, Cell Biology, biology.organism_classification, Protein Aggregation, Protein Structure, Tertiary, Fungal prion, nervous system diseases, MESH: Cell Line, Thiazoles, protéine prion, prion, amyloid, thiazoles, glycosylphosphatidylinositols, thioflavin T, biochemistry and molecular biology, Protein Multimerization, MESH: Prion, 030217 neurology & neurosurgery
Abstract

International audience; The concept of prion is applied to protein modules that share the ability to switch between at least two conformational states and transmit one of these through intermolecular interaction and change of conformation. Although much progress has been achieved through the understanding of prions from organisms such as Saccharomyces cerevisiae, Podospora anserina, or Aplysia californica, the criteria that qualify a protein module as a prion are still unclear. In addition, the functionality of known prion domains fails to provide clues to understand the first identified prion, the mammalian infectious prion protein, PrP. To address these issues, we generated mammalian cellular models of expression of the C-terminal two helices of PrP, H2 and H3, which have been hypothesized, among other models, to hold the replication and conversion properties of the infectious PrP. We found that the H2H3 domain is an independent folding unit that undergoes glycosylations and glycosylphosphatidylinositol anchoring similar to full-length PrP. Surprisingly, in some conditions the normally folded H2H3 was able to systematically go through a conversion process and generate insoluble proteinase K-resistant aggregates. This structural switch involves the assembly of amyloid structures that bind thioflavin S and oligomers that are reactive to A11 antibody, which specifically detects protein oligomers from neurological disorders. Overall, we show that H2H3 is a conformational switch in a cellular context and is thus suggested to be a candidate for the conversion domain of PrP.

Published
2011
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13. PrP assemblies: spotting the responsible regions in prion propagation

Author

Human Rezaei, Stéphanie Prigent, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), INRA-Package Fondation Alliance Biosecure, and Unité de recherche Virologie et Immunologie Moléculaires (VIM)

Subjects
Prions, animal diseases, polymer, [SDV]Life Sciences [q-bio], fibers, medicine.disease_cause, Fibril, Biochemistry, Protein Structure, Secondary, law.invention, protein aggregation, prion, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Protein structure, strain, law, medicine, Animals, Humans, domain of replication, Host protein, unfolding, MESH: prion, 030304 developmental biology, Commentary & View, 0303 health sciences, Mutation, Chemistry, amyloid, Cell Biology, Hydrogen-Ion Concentration, Protein multimerization, H2H3, MESH: aggregation, nervous system diseases, N-terminus, Infectious Diseases, MESH: secondary structure, MESH: protein, Biophysics, Recombinant DNA, Protein Multimerization, 030217 neurology & neurosurgery
Abstract

International audience; The "protein only" hypothesis states that the key phenomenon in prion pathogenesis is the conversion of the host protein (PrPC) into a beta-sheet enriched polymeric and pathogenic conformer (PrPSc). However the region of PrP bearing the information for structural transfer is still controversial. In a recent report, we highlighted the role of the C terminal part i.e. the helixes H2 and H3, using mutation approaches on recombinant PrP. The H2H3 was shown to be the minimal region necessary to reproduce the oligomerisation pattern of the full-length protein. The oligomers produced from isolated H2H3 domain presented the same structural characteristics as the oligomers formed from the full-length PrP. Combining other groups' results, this paper further discusses the relative, direct or indirect role of different PrP regions in assembly. The H2H3 region represents the core of PrP oligomers and fibrils, whereas the N terminus could explain divergences among different aggregates. Finally this review evocates the possibility to separate the domain involved in prion information transference (i.e. prion replication) from the domain bearing the cytotoxicity properties.

Published
2011
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14. Prion Fibrillization Is Mediated by a Native Structural Element That Comprises Helices H2 and H3

Author

Human Rezaei, A. Pastore, Céline Chapuis, Kris Pauwels, Zhou Xu, Stéphanie Prigent, Cesira de Chiara, Miquel Adrover, Structural Biology Research Center, VIB, 1050 Brussels, Belgium, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium]-VIB [Belgium], Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Molecular Structure, The National Institute for Medical Research, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Circular dichroism, Amyloid, Protein Denaturation, Protein Folding, Magnetic Resonance Spectroscopy, Prions, Protein Conformation, [SDV]Life Sciences [q-bio], Sequence (biology), Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Protein structure, Escherichia coli, Animals, Humans, Prion protein, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Sheep, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Circular Dichroism, Genetic Variation, Neurodegenerative Diseases, Cell Biology, Protein tertiary structure, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Kinetics, Microscopy, Electron, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Membrane protein, Biophysics, Chromatography, Gel, Thermodynamics, Protein folding, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, Molecular Biophysics
Abstract

Aggregation and misfolding of the prion protein (PrP) are thought to be the cause of a family of lethal neurodegenerative diseases affecting humans and other animals. Although the structures of PrP from several species have been solved, still little is known about the mechanisms that lead to the misfolded species. Here, we show that the region of PrP comprising the hairpin formed by the helices H2 and H3 is a stable independently folded unit able to retain its secondary and tertiary structure also in the absence of the rest of the sequence. We also prove that the isolated H2H3 is highly fibrillogenic and forms amyloid fibers morphologically similar to those obtained for the full-length protein. Fibrillization of H2H3 but not of full-length PrP is concomitant with formation of aggregates. These observations suggest a "banana-peeling" mechanism for misfolding of PrP in which H2H3 is the aggregation seed that needs to be first exposed to promote conversion from a helical to a beta-rich structure.

Published
2010
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