Aberrant Complement System Activation in Neurological Disorders

Abstract

The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overactivation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dysfunction of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system. Hence, the aim of this review is to provide a summary of the literature on the emerging role of the complement system in certain brain disorders.

Keywords: Huntington disease; Parkinson’s disease; amyotrophic lateral sclerosis; autism; cerebral ischaemia; complement system; epilepsy; multiple sclerosis; neurodegenerative diseases; schizophrenia; spinal cord injury; traumatic brain injury.

Figure 1

Activation of complement system. The complement system can be activated via three ways: classical, lectin, and alternative. The classical pathway is triggered by binding of the antibody-antigen complexes, apoptotic cells, CRP, Β-Amyloid, phospho-tau, or neuronal blebs to C1. The C1 is composed with C1q, C1r, and C1s, and binding of Cq1 with enumerated components changes the C1 conformation and activates C1s protease. The active C1s cleaves the C4 to C4a and C4b and C2 to C2a and C2, and forms C3 convertase—C4b2a which splits C3 into two fragments, C3b, which can opsonize microbial pathogens, and C3a, which activates mast cells and macrophages and promotes inflammation. The lectin pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues on the pathogen surface. This in turn activates the MBL-associated serine proteases, MASP-1/2, which activate C4 and C2 and form C4b2a. The C3b can bind to C4b2b to form the C5 convertase (C4b2a3b). C5 is cleaved to form C5a, which promotes inflammation, and C5b, which binds to C6, C7, C8, and C9 and forms the membrane attack complex (MAC) which enables cell lysis. The alternative pathway is triggered by hydrolysis of C3 to C3-H₂O; then, factors B and D generate the C3 convertase—C3(H₂O)Bb, which cleaves other C3 molecules to C3a and C3b. This in turn forms C3bBb complex which continues cleavage of the C3 and enables formation of the C5 convertase—C3bBb3b, which cleaves C5 and leads to the formation of the MAC.