Abstract
BackgroundGlaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex.MethodsTo assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence.ResultsC5-sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina.ConclusionC5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma.
Highlights
Glaucoma, the second leading cause of blindness worldwide, is a neurodegenerative disease involving the death of retinal ganglion cells (RGCs) and degeneration of the optic nerve [1,2,3]
D2.C5B6 mice develop a disease of the iris and a glaucomatous intraocular pressure (IOP) profile DBA/2J (D2) mice do not express a functional C5 protein, owing to a frameshift mutation in the C5 gene [26]
D2 mice develop a secondary glaucoma as a result of an iris disease, Figure 1 Progression of iris disease and intraocular pressure (IOP) profiles in DBA/2J and D2.C5B6 mice. (A) The congenic interval surrounding C5 in D2.C5B6 mice determined using markers polymorphic between D2 and B6
Summary
The second leading cause of blindness worldwide, is a neurodegenerative disease involving the death of retinal ganglion cells (RGCs) and degeneration of the optic nerve [1,2,3]. A number of processes have been implicated in glaucoma, but the key molecules that mediate early damage remain unclear. C5a is an anaphylotoxin that can mediate neuroinflammatory responses, while C5b is a key molecule in the formation of the membrane attack complex (MAC). Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. The complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex
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