Complement protein C1q forms a complex with cytotoxic prion protein oligomers.
A growing number of studies have investigated the interaction between C1q and PrP, but the oligomeric form of PrP involved in this interaction remains to be determined. Aggregation of recombinant full-length murine PrP in the presence of 100 mm NaCl allowed us to isolate three different types of oligomers by size-exclusion chromatography. In contrast to PrP monomers and fibrils, these oligomers activate the classical complement pathway, the smallest species containing 8-15 PrP protomers being the most efficient. We used Thioflavine T fluorescence to monitor PrP aggregation and showed that, when added to the reaction, C1q has a cooperative effect on PrP aggregation and leads to the formation of C1q-PrP complexes. In these complexes, C1q interacts through its globular domains preferentially with the smallest oligomers, as shown by electron microscopy, and retains the ability to activate the classical complement pathway. Using two cell lines, we also provide evidence that C1q inhibits the cytotoxicity induced by the smallest PrP oligomers. The cooperative interaction between C1q and PrP could represent an early step in the disease, where it prevents elimination of the prion seed, leading to further aggregation.
Erlich
Paul
P
Laboratoire Adaptation et Pathogénie des Micro-organismes, Université Joseph Fourier, 38042 Grenoble cedex 9, France.
Dumestre-Pérard
Chantal
C
Ling
Wai Li
WL
Lemaire-Vieille
Catherine
C
Schoehn
Guy
G
Arlaud
Gérard J
GJ
Thielens
Nicole M
NM
Gagnon
Jean
J
Cesbron
Jean-Yves
JY
D000682:Amyloid / Q000737:chemistry; D000818:Animals; D052160:Benzothiazoles; D002845:Chromatography / Q000379:methods; D015922:Complement C1q / Q000378:metabolism*; D003181:Complement C4 / Q000737:chemistry; D003165:Complement System Proteins; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008854:Microscopy, Electron / Q000379:methods; D009474:Neurons / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D013844:Thiazoles / Q000737:chemistry
D000682:Amyloid; D052160:Benzothiazoles; D003181:Complement C4; D011328:Prions; D013844:Thiazoles; C009462:thioflavin T; D015922:Complement C1q; D003165:Complement System Proteins
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