Increasing evidence suggests that neuroinflammation in both the central nervous system and periphery contributes to pathophysiology and disease progression of ALS. In addition, both preclinical and clinical studies implicate a role for the complement system in the neuroinflammatory response observed in ALS, although mechanistic details are lacking. The overall goal of this proposal is to investigate the role of complement in the progression and pathophysiology of disease in ALS mouse models using a novel approach of complement inhibition. Complement inhibition will be evaluated for therapeutic potential, while at the same time used as an investigative tool to better understand the role of complement in ALS. Although clinical trials using complement inhibitors to treat ALS have recently been announced, the approach we will investigate offers significant potential advantages over the inhibitors entering clinical trials. The specific aims are to examine the role of complement and the effect of targeted C3 inhibition on disease progression and survival, and to determine complement- dependent pathophysiology and inflammatory/immune profiles during disease progression. It is expected that data generated will provide the foundation on which to build more detailed mechanistic investigations, as well develop novel complement-inhibitory therapeutic approaches that could be addressed in a Merit application. There is no effective treatment for ALS, and our therapeutic strategy has the potential to be beneficial at multiple levels by directly protecting motor neurons from complement activation in the CNS, by protecting motor end- plates, and by potentially modifying glia-motor neuron interactions.