title: Activation of classical pathway of complement cascade by soluble oligomers of prion.
abstract: Mice defective for C1q complement factor show enhanced resistance to peripheral prion inoculation, and previous work demonstrated a direct interaction between C1q and conformationally modified PrP. However, the nature and physiological consequences of this interaction remain uncharacterized. PrP amino acids 141-159 has been identified as a potential C1q binding site; we show, by both surface plasmon resonance (SPR) spectroscopy and ELISA, that C1q and its globular region bind to PrP mutagenized in the region of interest with comparable efficiency to that of wild-type protein. To test PrP's ability to activate complement, soluble oligomers of the PrP constructs were made. Only PrP and mutagenized PrP oligomers activate the classical complement cascade while PrP monomer and the C-terminal domain, both in oligomeric and in monomeric form, failed to induce activation. This suggests that a conformational change in PrP, which occurs both when PrP is bound to an SPR sensor chip and when it undergoes oligomerization, is requisite for PrP/C1q interaction and activation of the complement cascade. We propose that C1q may act as a natural sensor for prions, leading to activation of the classical complement cascade, which could result in local inflammation and subsequent recruitment of the immune cells that prions initially infect.
authors.affiliation: Laboratoire d'Adaptation et Pathogenèse des Microorganismes, UMR5163 CNRS-UJF, Institut Jean Roget, BP170, 38042 Grenoble cedex 9, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dumestre-Pérard
authors.forename: Joseph
authors.initials: J
authors.lastname: Osmundson
authors.forename: Catherine
authors.initials: C
authors.lastname: Lemaire-Vieille
authors.forename: Nicole
authors.initials: N
authors.lastname: Thielens
authors.forename: Audrey
authors.initials: A
authors.lastname: Grives
authors.forename: Bertrand
authors.initials: B
authors.lastname: Favier
authors.forename: Françoise
authors.initials: F
authors.lastname: Csopaki
authors.forename: Marc
authors.initials: M
authors.lastname: Jamin
authors.forename: Jean
authors.initials: J
authors.lastname: Gagnon
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cesbron
mesh_terms: D000818:Animals; D015922:Complement C1q / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D016296:Mutagenesis; D011328:Prions / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D020349:Surface Plasmon Resonance
chemical_list: D011328:Prions; D015922:Complement C1q