Emerging Roles of Complement Protein C1q in Neurodegeneration

Abstract

The innate immune system is an ancient and primary component system that rapidly reacts to defend the body against external pathogens. C1 is the initial responder of classical pathway of the innate immune system. C1 is comprised of C1q, C1r, and C1s. Among them, C1q is known to interact with diverse ligands, which can perform various functions in physiological and pathophysiological conditions. Because C1q participates in the clearance of pathogens, its interaction with novel receptors is expected to facilitate apoptosis induction, which could prevent the onset or progression of neurodegenerative diseases and could delay the aging process. Because senescence-associated secreting phenotype determinants are generally inflammatory cytokines or immune factors to activate immune cells. In the central nervous system, C1q has diverse neuroprotective roles against pathogens and inflammation. Most of neurodegenerative diseases show region specific pathology feature in the brain. It has been suggested the evidences that the active site and amount of C1q may be disease specific. This review considers currently the emerging and under-recognized roles of C1q in neurodegeneration and highlights the need for further research to clarify these roles. Future studies on the roles of C1q in regulating disease progression should consider these aspects, including the age-dependent onset time of each neurodegenerative disease progression.

Keywords: C1q; aging; astrocyte; innate immunity; microglia; neurodegenerative disease; neuron; synaptic pruning.

Figure 1.. Structural form and biological functions of C1q

(A) C1q consists of globular heads (gC1q) and a collagen-like region (cC1q). (B) The diagrammatic circle is presenting the functional hallmark of C1q.

Figure 2.. C1q in the CNS aging process

Systemic changes due to aging occur as aged neurons are degenerated by the activation of surveillance microglia. Increased C1q that accompanies aging factors, but not the increased amount itself, may contribute to the aging progression of neurons. CNS-derived C1q is thought to correspond to physiological changes known as senescence-associated secreting phenotype determinants, which are relevant to ROS, DNA damages, and inflammatory cytokines. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern.

Figure 3.

Pathophysiological implications of C1q in neurodegenerative diseases. C1q is involved in the pathological pathway in each neurodegenerative disease due to its role in abnormal protein aggregate clearance, astrocyte reactivation, binding and activation of microglia, or inflammatory responses. C1q in the age-dependent onset time of each neurodegenerative disease participates in regulating disease progression. AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease; PrP, prion protein; DC, dendritic cell.