C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

Abstract

Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including C1q, C4, and C3) in spinal cords of SOD1 mutantexpressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the C1q gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q-deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q-and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice.amyotrophic lateral sclerosis | motoneuron | synaptic density | gender differences | neuroinflammation

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…Complement factors are mostly synthesized in the liver, but in mSOD1 transgenic animal models, complement factor C1q transcription was noted to be upregulated in motor neurons [102]. However, the role of the complement pathway still remains controversial [103][104][105][106]. The role of peripheral monocytes in ALS is also controversial.…”

The role of complement system in amyotrophic lateral sclerosis

“…By contrast to the above studies, which indicates a role for the classical complement pathway in the progression of pathology of the hSOD1 transgenic mouse, recent studies have demonstrated that when hSOD1 transgenic mice were bred onto a background deficient in complement C1q, C3 and C4, there was no difference in the onset of motor symptoms and survival when compared to hSOD1 transgenic mice (Chiu et al, 2009, Lobsiger et al, 2013. These studies indicate that blocking upstream complement activation pathways does not alter the disease course in hSOD1 transgenic mice.…”

“…Intriguingly, recent studies have shown deletion of C1q, C3 and C4 in hSOD1 transgenic mouse models did not show any beneficial effects on the disease progression of ALS (Chiu et al, 2009, Lobsiger et al, 2013.…”

“…shown that inhibition of upstream complement components C1q, C3 and C4 in hSOD1 transgenic mouse models did not show any beneficial effects on the disease progression of ALS (Chiu et al, 2009, Lobsiger et al, 2013. Hence, these combined studies indicate that blocking upstream complement activation pathways does not alter the disease course in hSOD1 transgenic mice.…”

“…However, deletion of C1q, C3 and C4 in hSOD1 transgenic mouse models did not show any beneficial effects on the disease progression of ALS, which indicates that blocking upstream complement activation pathways does not contribute to ALS mice neurotoxicity (Chiu et al, 2009, Lobsiger et al, 2013. This introduces the possibility that downstream complement factors (C3 and C5) potentially generated by the fourth "extrinsic pathway", may play a role in the disease progression of ALS.…”