Publications by authors named "Celine Chapuis"

6 Publications

  • Page 1 of 1

Emergence of two prion subtypes in ovine PrP transgenic mice infected with human MM2-cortical Creutzfeldt-Jakob disease prions.

Acta Neuropathol Commun 2016 Feb 5;4:10. Epub 2016 Feb 5.

INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.

Introduction: Mammalian prions are proteinaceous pathogens responsible for a broad range of fatal neurodegenerative diseases in humans and animals. These diseases can occur spontaneously, such as Creutzfeldt-Jakob disease (CJD) in humans, or be acquired or inherited. Prions are primarily formed of macromolecular assemblies of the disease-associated prion protein PrP(Sc), a misfolded isoform of the host-encoded prion protein PrP(C). Within defined host-species, prions can exist as conformational variants or strains. Based on both the M/V polymorphism at codon 129 of PrP and the electrophoretic signature of PrP(Sc) in the brain, sporadic CJD is classified in different subtypes, which may encode different strains. A transmission barrier, the mechanism of which remains unknown, limits prion cross-species propagation. To adapt to the new host, prions have the capacity to 'mutate' conformationally, leading to the emergence of a variant with new biological properties. Here, we transmitted experimentally one rare subtype of human CJD, designated cortical MM2 (129 MM with type 2 PrP(Sc)), to transgenic mice overexpressing either human or the VRQ allele of ovine PrP(C).

Results: In marked contrast with the reported absence of transmission to knock-in mice expressing physiological levels of human PrP, this subtype transmitted faithfully to mice overexpressing human PrP, and exhibited unique strain features. Onto the ovine PrP sequence, the cortical MM2 subtype abruptly evolved on second passage, thereby allowing emergence of a pair of strain variants with distinct PrP(Sc) biochemical characteristics and differing tropism for the central and lymphoid tissues. These two strain components exhibited remarkably distinct replicative properties in cell-free amplification assay, allowing the 'physical' cloning of the minor, lymphotropic component, and subsequent isolation in ovine PrP mice and RK13 cells.

Conclusions: Here, we provide in-depth assessment of the transmissibility and evolution of one rare subtype of sporadic CJD upon homologous and heterologous transmission. The notion that the environment or matrix where replication is occurring is key to the selection and preferential amplification of prion substrain components raises new questions on the determinants of prion replication within and between species. These data also further interrogate on the interplay between animal and human prions.
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http://dx.doi.org/10.1186/s40478-016-0284-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743415PMC
February 2016

Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders.

Hum Mol Genet 2012 Dec 10;21(26):5417-28. Epub 2012 Sep 10.

AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisiére et Universite´ Paris Descartes, Paris, France.

Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.
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http://dx.doi.org/10.1093/hmg/dds377DOI Listing
December 2012

The oligomerization properties of prion protein are restricted to the H2H3 domain.

FASEB J 2010 Sep 21;24(9):3222-31. Epub 2010 Apr 21.

Institut National de la Recherche Agronomique, Virologie et Immunologie Moléculaires, INRA, F-78352 Jouy-en-Josas, France.

The propensity of the prion protein (PrP) to adopt different structures is a clue to its pathological behavior. The determination of the region involved in the PrP(C) to PrP(Sc) conversion is fundamental for the understanding of the mechanisms underlying this process at the molecular level. In this paper, the polymerization of the helical H2H3 domain of ovine PrP (OvPrP) was compared to the full-length construct (using chromatography and light scattering). We show that the oligomerization patterns are identical, although the H2H3 domain has a higher polymerization rate. Furthermore, the depolymerization kinetics of purified H2H3 oligomers compared to those purified from the full-length PrP reveal that regions outside H2H3 do not significantly contribute to the oligomerization process. By combining rational mutagenesis and molecular dynamics to investigate the early stages of H2H3 oligomerization, we observe a conformationally stable beta-sheet structure that we propose as a possible nucleus for oligomerization; we also show that single point mutations in H2 and H3 present structural polymorphisms and oligomerization properties that could constitute the basis of species or strain variability.
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http://dx.doi.org/10.1096/fj.09-153924DOI Listing
September 2010

Prion fibrillization is mediated by a native structural element that comprises helices H2 and H3.

J Biol Chem 2010 Jul 7;285(27):21004-12. Epub 2010 Apr 7.

MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, United Kingdom.

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.
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http://dx.doi.org/10.1074/jbc.M110.111815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898372PMC
July 2010