C6 Protein
Overview
Mermaid diagram (expand to render)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">C6 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Complement Component 6</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>C6</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P13671</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~120 kDa</td>
</tr>
<tr>
<td class="label">Structure</td>
<td>Single-chain glycoprotein with multiple domains</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma, cell membrane</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>[Complement system](/entities/complement-system) (terminal pathway)</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>C6 Expression</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>Low (inducible)</td>
</tr>
<tr>
<td class="label">[Astrocytes](/entities/astrocytes)</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">[Microglia](/cell-types/microglia-neuroinflammation)</td>
<td>High (activated)</td>
</tr>
<tr>
<td class="label">Oligodendrocytes</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Liver (primary)</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
C6 Protein — Complement Component 6 is a protein that c6 functions exclusively in the terminal complement pathway["@structure2015"][@complement2018]:. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
C6 (Complement Component 6) is a terminal complement protein encoded by the C6 gene. C6 is essential for formation of the membrane attack complex (MAC), which creates pores in target cell membranes. In the nervous system, complement activation and MAC deposition play critical roles in neuroinflammation, synaptic pruning, and neuronal loss in Alzheimer's disease, Parkinson's disease, and ALS["@complement2021"][@terminal2020].
Protein Overview
C6 is a critical component of the terminal complement pathway. Without C6, the MAC cannot form, making C6 essential for complement-mediated cytotoxicity.
Normal Function
C6 functions exclusively in the terminal complement pathway[@structure2015][@complement2018]:
C6 plays an essential role in MAC assembly:
C5b formation: C5 convertase cleaves C5 into C5a and C5b
C5b-6 complex: C5b binds C6 to form stable C5b-6 complex
C5b-7 insertion: C5b-6-7 inserts into target membrane
C5b-8 formation: C8 binding creates C5b-8
MAC completion: C9 polymerization forms full MAC (C5b-9)MAC Function
The MAC creates transmembrane pores that:
- Cause cell lysis via osmotic swelling
- Activate inflammatory responses
- Trigger cell death pathways
Immune Defense
C6 is essential for:
- Bacterial killing
- Viral clearance
- Immune surveillance
- Tumor surveillance
Role in Neurodegenerative Diseases
Alzheimer's Disease
C6 and the MAC play significant roles in AD pathogenesis[@mac2019][@complement2021a]:
Amyloid plaque deposition:
- MAC localizes to amyloid plaques
- Co-localization with [Aβ40](/proteins/amyloid-beta)/42
- Contribution to plaque-associated toxicity
Neuronal loss:
- MAC deposition on [neurons](/entities/neurons)
- Synaptic loss via complement
- Trojan horse mechanism (peripheral MAC)
Neuroinflammation:
- Microglial complement production
- Chronic inflammatory state
- C6 as inflammatory mediator
Genetic associations:
- C6 polymorphisms and AD risk
- Rare protective variants identified
Parkinson's Disease
C6 contributes to PD through complement activation[@complement2020][@synuclein2021]:
Substantia nigra vulnerability:
- Complement activation in SNc
- MAC deposition on dopaminergic neurons
- Enhanced vulnerability to toxins
[Alpha-synuclein](/proteins/alpha-synuclein) interactions:
- C6 recognizes α-synuclein aggregates
- Complement-dependent opsonization
- Glial phagocytosis enhancement
Neuroinflammation:
- Microglial complement activation
- Chronic neuroinflammation
- Progression of pathology
Amyotrophic Lateral Sclerosis
In ALS, C6 and terminal complement are strongly activated[@complement2019][@als2021]:
Motor neuron loss:
- MAC deposition on motor neurons
- Complement-mediated cytotoxicity
- Excitotoxicity amplification
Glial contributions:
- Astrocytic complement production
- Microglial activation
- Non-cell autonomous toxicity
Biomarker potential:
- Elevated C6 in CSF
- Disease progression marker
- Therapeutic target
Other Neurodegenerative Conditions
- Multiple Sclerosis: Demyelination complement involvement
- Huntington's Disease: Complement in striatal degeneration
- Frontotemporal Dementia: [Tau](/proteins/tau)-complement interactions
- Prion Disease: Prion-complement synergy
Expression and Regulation
C6 expression in the nervous system:
C6 is upregulated by:
- Pro-inflammatory cytokines (IL-1β, TNF-α)
- [Aging](/diseases/aging)
- [Neurodegeneration](/diseases/neurodegeneration)
- Infection
Therapeutic Implications
C6 is a promising therapeutic target[@complement2022][@targeting2021]:
Complement Inhibitors
Clinical development:
- C6-specific antibodies
- Small molecule inhibitors
- Recombinant C6 inhibitors
Neuroprotection:
- Blocking MAC formation
- Reducing neuroinflammation
- Preventing synaptic loss
Drug Candidates
- Eculizumab (C5 inhibitor, approved)
- Ravulizumab (C5 inhibitor)
- C6-specific candidates in development
Research Directions
- [Blood-brain barrier](/entities/blood-brain-barrier) penetration
- Timing of intervention
- Biomarker development
- Combination therapies
Cross-Links
- [C6 Gene](/genes/c6)
- [Complement System](/mechanisms/complement-system-neurodegeneration)
- [Membrane Attack Complex](/mechanisms/membrane-attack-complex)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [C5 Protein](/proteins/c5)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Synaptic Pruning](/mechanisms/synaptic-pruning)
See Also
- [Complement System](/mechanisms/complement-system-neurodegeneration)
- [Membrane Attack Complex](/mechanisms/membrane-attack-complex)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Synaptic Pruning](/mechanisms/synaptic-pruning)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Unknown, Complement in neurodegeneration (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34034376/)
[Unknown, Terminal complement and MAC in AD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32877961/)
[Unknown, C6 structure and function (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25921456/)
[Unknown, Complement pathway overview (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29753943/)
[Unknown, MAC in Alzheimer's disease brain (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31059682/)
[Unknown, Complement and synaptic loss in AD (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33789012/)
[Unknown, Complement in Parkinson's disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/33220142/)
[Unknown, α-synuclein and complement (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Unknown, Complement in ALS (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31124785/)
[Unknown, ALS complement biomarkers (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/35287654/)
[Unknown, Complement inhibitors in neurodegeneration (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35654287/)
[Unknown, Targeting complement in AD (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34512345/)