PROJECT SUMMARY Historically largely focused on the demise of neurons, a wealth of literature in the neurodegeneration field has provided strong evidence for a critical role of neuroinflammation. It is now well established that both astro- and microgliosis contribute to disease onset and/or progression. These glial cells can directly respond to the aggregate/condensate pathology that characterizes these conditions and this has been suggested to underlie their hyperinflammation. Yet, why this happens has been puzzling as humans never experienced selective pressure to evolve the ability to detect age-related pathology. Why do glia respond to something they have never been trained to respond to? The immune system did evolve detection systems for infection, and the evolutionary arms race between humans and their pathogens has shaped a plethora of receptors and signaling cascades that are involved in the sensing of and immediate response to infection. This is the innate immune system. Recently, I unexpectedly discovered that some of these neuropathological proteins mimic the biophysical behavior of innate immune signals. Antimicrobial peptides—mostly known for their killer activity towards pathogens—also moonlight as pro-inflammatory signals. More specifically, these cationic peptides can promote the immunogenicity of nucleic acids towards their Toll-like receptors, in a process that is dependent on the electrostatic condensation of such peptides with the anionic nucleic acids. Condensing these immunogens concentrates them, protects them from degradation, and drives their trafficking to their corresponding receptor— hereby dramatically boosting the inflammatory response. Neuropathological proteins from many diseases condense or aggregate with nucleic acids, suggesting that such potent immune triggers are commonly found in the diseased brain. We show that the pathology associated with the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia indeed signals to the innate immune system via this condensation- dependent mechanism. Thus, I propose the provocative idea that neuropathology in general must hijack such ancient immune signaling cascades to trigger the immune system. This hypothesis provides and elegant explanation of the decades-old question of the molecular origins of neuroinflammation. In this proposal, my lab will set out to rigorously test this hypothesis using a multidisciplinary approach that spans from biophysics to in vivo disease modeling. By leveraging our expertise in condensate biology, building on preliminary data from our genetics- and proteomics-based approaches, and using in vitro and in vivo models, we will uncover the biophysical rules and signaling cascades underlying this molecular mimicry. Neuroinflammation is a key modifier of disease progression. If successful, we will identify promising new candidates and compounds for therapeutic neuro-immunomodulation in these devastating diseases.