Complement protein C1q forms a complex with cytotoxic prion protein oligomers
Paul Erlich1, Chantal Dumestre-Pérard, Wai Li Ling
1Laboratoire Adaptation et Pathogénie des Micro-organismes, Université Joseph Fourier, 38042 Grenoble cedex 9, France.
The Journal of Biological Chemistry
|April 23, 2010
Summary
The complement protein C1q interacts with specific prion protein (PrP) oligomers, activating the complement pathway. This interaction may hinder prion clearance, potentially contributing to disease progression.
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- The interaction between C1q and prion protein (PrP) is under investigation.
- The specific oligomeric forms of PrP involved in C1q binding are not well-defined.
Purpose of the Study:
- To identify the oligomeric forms of PrP that interact with C1q.
- To investigate the functional consequences of C1q-PrP interactions on complement activation and cytotoxicity.
Main Methods:
- Recombinant murine PrP aggregation induced by NaCl.
- Size-exclusion chromatography for oligomer isolation.
- Thioflavine T fluorescence for aggregation monitoring.
- Electron microscopy for C1q-PrP complex visualization.
- Cell-based assays to assess cytotoxicity.
Main Results:
- Three distinct PrP oligomer types were isolated, differing from monomers and fibrils.
- These PrP oligomers activate the classical complement pathway, with smaller oligomers (8-15 protomers) being most potent.
- C1q exhibits a cooperative effect on PrP aggregation, forming C1q-PrP complexes.
- C1q preferentially binds to smaller PrP oligomers via its globular domains.
- C1q retains complement-activating ability within these complexes.
- C1q inhibits the cytotoxicity induced by the smallest PrP oligomers in cell lines.
Conclusions:
- Specific PrP oligomers, not monomers or fibrils, activate the classical complement pathway.
- C1q binding to PrP oligomers enhances aggregation and complement activation.
- This C1q-PrP interaction may impede prion clearance, potentially initiating or exacerbating disease processes.
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