C1QA is a protein encoded by the C1QA gene, serving as a key component of the human complement system. Along with C1r and C1s, it forms the C1 complex, the initial component of this system. C1QA is composed of 18 polypeptide chains: six A-chains, six B-chains, and six C-chains. Each chain features a collagen-like region near its N-terminus and a globular region at its C-terminus.
C1QA’s Role in Immunity
C1QA plays a primary role in the body’s immune defense by initiating the classical pathway of the complement system. The complement system is a complex network of proteins that eliminate pathogens and maintain immune balance. As part of the C1 complex, C1QA recognizes and binds to specific targets like antibody-antigen complexes on the surface of pathogens. It also binds to other ligands, including bacterial and viral surface proteins, and proteins associated with acute phase responses.
When C1QA binds to these targets, it triggers a series of events within the C1 complex. This binding causes conformational changes in C1QA, which activates C1r, a proenzyme. Activated C1r then cleaves C1s, another proenzyme, initiating a proteolytic cascade. This cascade marks pathogens for destruction and helps clear cellular debris, ultimately leading to the formation of a C3 convertase. This further amplifies the immune response by cleaving C3, a major component of the complement system.
Beyond its direct role in pathogen clearance, C1QA also participates in removing cellular waste, such as apoptotic (dying) cells. C1QA binds to phosphatidylserine, a molecule exposed on the surface of apoptotic cells, promoting their recognition and removal by phagocytes. This process prevents the accumulation of dead cells and their contents, which could otherwise trigger unwanted inflammatory responses or autoimmune reactions. C1QA’s involvement in regulating cell processes further highlights its role in maintaining immune balance.
C1QA’s Role in Brain Function
C1QA also performs an important function within the central nervous system. It is involved in synaptic pruning, the selective elimination of unnecessary or weak synaptic connections between neurons. This process is particularly important during brain development, where an excess of synaptic connections initially forms. Synaptic pruning refines neural circuits, leading to more efficient and precise brain function.
During development, C1QA, along with other complement components like C3 and C4, tags specific synapses for elimination. These tagged synapses are then recognized and engulfed by microglia, the brain’s resident immune cells, through phagocytosis. This microglia-mediated synaptic pruning helps sculpt the developing brain’s wiring.
While synaptic pruning is most prominent in early life, C1QA continues to contribute to synaptic plasticity in the adult brain, including processes related to memory. The presence of C1QA at synapses acts as a molecular “tag” that guides microglia in selectively removing less active or inappropriate connections. This ongoing refinement helps maintain healthy neural networks and supports adaptive brain functions throughout life.
When C1QA Goes Awry: Health Implications
Dysfunction in C1QA can have significant health consequences, leading to both autoimmune diseases and neurodegenerative disorders. When C1QA is deficient or its function is impaired, the body’s ability to clear immune complexes and apoptotic cells is compromised. This impaired clearance can result in the accumulation of cellular debris and self-antigens, which may trigger autoimmune responses. For example, a deficiency in C1QA is strongly associated with Systemic Lupus Erythematosus (SLE), an autoimmune disease where the body attacks its own tissues. More than 90% of individuals with C1q deficiency may develop SLE.
In SLE, the accumulation of autoantibodies and apoptotic cells is common. Antibodies targeting C1q itself are also frequently found in individuals with SLE, especially those with kidney involvement. These anti-C1q antibodies can contribute to disease activity and are sometimes used as a diagnostic marker. The link between C1QA deficiency and SLE highlights its importance in maintaining immune tolerance and preventing the body from attacking its own healthy components.
In the brain, dysregulation of C1QA’s role in synaptic pruning and neuroinflammation can contribute to neurodegenerative conditions. While C1QA is normally involved in healthy synaptic refinement, its excessive or dysregulated activity can lead to detrimental synapse loss in the adult brain. Increased C1q levels have been observed during normal aging in the brain, localizing near synapses. This suggests a possible role in age-related synaptic decline.
C1QA-mediated synaptic loss has been implicated in early stages of neurodegenerative diseases such as Alzheimer’s disease and glaucoma. In Alzheimer’s disease, increased complement pathway activation may contribute to neuronal damage. Similarly, in glaucoma, a neurodegenerative disease affecting the optic nerve, C1q-dependent synaptic pruning may contribute to synapse loss. The presence of C1q and C3 deposition at synapses has been associated with excessive synaptic pruning in conditions like multiple sclerosis, leading to synaptic loss and functional impairments.