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

Lobsiger, Christian S., Boillée, Severine, Pozniak, Christine, Khan, Amir M., McAlonis-Downes, Melissa, Lewcock, Joseph W., Cleveland, Don W.
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.46 pp. E4385
animal models, complement, disease course, genes, immune response, innate immunity, mice, motor neurons, mutants, mutation, nerve tissue, pathogenesis, superoxide dismutase, toxicity
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 mutant-expressing 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.