C1q binding and complement activation by prions and amyloids

Sim, Robert B.; Kishore, Uday; Villiers, Christian; Marche, Patrice N.; Mitchell, Daniel A.

doi:10.1016/j.imbio.2007.04.001

Cited by 47 publications

(39 citation statements)

References 46 publications

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“…C1q binds via its globular heads to a wide range of foreign or altered self-targets. These include Gram-negative bacteria, several viruses, apoptotic cells and products of tissue damage, and certain aggregates such as IgG-and IgM-containing immune complexes, and also amyloids (15,16). Additionally C1q can act as an opsonin (17).…”

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confidence: 99%

Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells

Flores‐Langarica

Sebti

Mitchell

et al. 2009

The Journal of Immunology

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Mice lacking complement components show delayed development of prion disease following peripheral inoculation. The delay could relate to reduced scrapie prion protein (PrPSc) accumulation on follicular dendritic cells (DCs). However conventional DCs (cDCs) play a crucial role in the early pathogenesis of prion diseases and complement deficiency could result in decreased PrPSc uptake by cDCs in the periphery. To explore this possibility, we cultured murine splenic or gut-associated lymph node cDCs with scrapie-infected whole brain homogenate in the presence or absence of complement. Uptake decreased significantly if the serum in the cultures was heat-inactivated. Because heat inactivation primarily denatures C1q, we used serum from C1q−/− mice and showed that PrPSc uptake was markedly decreased. PrPSc internalization was saturable and temperature-dependent, suggesting receptor-mediated uptake. Furthermore, uptake characteristics differed from fluid-phase endocytosis. Immunofluorescence showed colocalization of C1q and PrPSc, suggesting interaction between these molecules. We evaluated the expression of several complement receptors on cDCs and confirmed that cDCs that take up PrPSc express one of the C1q receptors, calreticulin. Our results show that C1q participates in PrPSc uptake by cDCs, revealing a critical role for cDCs in initial prion capture, an event that takes place before the PrPSc accumulation within the follicular DC network.

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confidence: 99%

Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells

Flores‐Langarica

Sebti

Mitchell

et al. 2009

The Journal of Immunology

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“…C1q binds PrP C in a conformation-and density-dependent manner and PrP Sc activates the classical complement pathway (48,49). Cleavage products of the soluble complement proteins C3 and C4 covalently attach to microbial surfaces and immune complexes, which are then presented as Ags on the surface of B cells and FDCs via the complement receptors CD21/35 (50 -52).…”

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confidence: 99%

Stromal Complement Receptor CD21/35 Facilitates Lymphoid Prion Colonization and Pathogenesis

Zabel

Heikenwälder

Prinz

et al. 2007

The Journal of Immunology

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We have studied the role of CD21/35, which bind derivatives of complement factors C3 and C4, in extraneural prion replication and neuroinvasion. Upon administration of small prion inocula, CD21/35−/− mice experienced lower attack rates and delayed disease over both wild-type (WT) mice and mice with combined C3 and C4 deficiencies. Early after inoculation, CD21/35−/− spleens were devoid of infectivity. Reciprocal adoptive bone marrow transfers between WT and CD21/35−/− mice revealed that protection from prion infection resulted from ablation of stromal, but not hemopoietic, CD21/35. Further adoptive transfer experiments between WT mice and mice devoid of both the cellular prion protein PrPC and CD21/35 showed that splenic retention of inoculum depended on stromal CD21/35 expression. Because both PrPC and CD21/35 are highly expressed on follicular dendritic cells, CD21/35 appears to be involved in targeting prions to follicular dendritic cells and expediting neuroinvasion following peripheral exposure to prions.

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“…C1q in the Aggregation Process of PrP-Investigation of the functional relevance of the C1q-PrP interaction has focused on the ability of PrP-derived ligands to interact with complement factors and trigger complement activation (19,20,23). In the present study, we characterized a novel role for C1q, namely its ability to interact with PrP during the process of oligomer formation and to enhance this process in a dose-dependent manner.…”

Section: C1q Binds Preferentially To Small Prp Oligomers-mentioning

confidence: 88%

“…Further studies have described direct interaction between C1q and PrP (19,20,22,23). However, the nature of the PrP isoform (i.e.…”

Section: C1q Binds Preferentially To Small Prp Oligomers-mentioning

confidence: 99%

Complement Protein C1q Forms a Complex with Cytotoxic Prion Protein Oligomers

Erlich

Dumestre-Pérard

Ling

et al. 2010

Journal of Biological Chemistry

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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.Prion diseases represent a group of singular transmissible neurodegenerative disorders that affect mammals and occur when the cellular prion protein (PrP c ) 2 is converted into an abnormal aggregated isoform called PrP Sc (1). The host PrP c is an ␣-helix-rich 30 -35-kDa glycoprotein expressed mainly in neuronal tissues in humans and other animals (2). Its expression and membrane attachment through a glycosylphosphatidyl anchor are crucial for transmissible spongiform encephalopathy susceptibility (3). The widely supported protein-only hypothesis stipulates that the infectious agent can replicate by converting the natively folded prion protein (PrP c ). During the disease, changes occur in the secondary and tertiary structure of PrP c , resulting in an increased content of the ␤-sheet, which leads to the formation of aggregates that display a dramatic shift in their physicochemical properties compared with those of the original protein (4). These ␤-sheet-rich aggregates are resistant to degradation by proteases and tend to form oligomers that can further assemble into amyloid fibrils. Recent investigations support the hypothesis that in protein misfolding and aggregation pathologies like Alzheimer disease, smaller subfibrillar particles may be much more pathological than larger amyloid fibrils or plaques (5). In line with this hypothesis, Silveira and colleagues have reported that the smallest aggregate able to initiate transmissible spongiform encephalopathies pathology is equivalent to ϳ14 -28 PrP molecules (6). In the past, several in vitro recombinant models have been used to investigate the biochemical and biophysical properties of such oligomeric intermediates (7-10). C1q is the first component of the classical complement pathway. C1q binds to many non-self and altered-self-materials. These include mi...

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C1q binding and complement activation by prions and amyloids

Cited by 47 publications

References 46 publications

Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells

Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells

Stromal Complement Receptor CD21/35 Facilitates Lymphoid Prion Colonization and Pathogenesis

Complement Protein C1q Forms a Complex with Cytotoxic Prion Protein Oligomers

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