Activation of classical pathway of complement cascade by soluble oligomers of prion.
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.
Dumestre-Pérard
Chantal
C
Laboratoire d'Adaptation et Pathogenèse des Microorganismes, UMR5163 CNRS-UJF, Institut Jean Roget, BP170, 38042 Grenoble cedex 9, France.
Osmundson
Joseph
J
Lemaire-Vieille
Catherine
C
Thielens
Nicole
N
Grives
Audrey
A
Favier
Bertrand
B
Csopaki
Françoise
F
Jamin
Marc
M
Gagnon
Jean
J
Cesbron
Jean-Yves
JY
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
D011328:Prions; D015922:Complement C1q