Background: Neurodegenerative diseases with tau pathology (tauopathies) include Alzheimer's disease and chronic traumatic encephalopathy. Two major risk factors for developing tauopathies are aging and repetitive mild traumatic brain injury. The prevalence of tauopathies is expected to rise, especially among Veterans. However, there are no clinically-approved treatments for tauopathies. DOPA decarboxylase, the second enzyme in dopamine and serotonin synthesis, was recently identified as a novel genetic modulator of tauopathy in a Caenorhabditis elegans model. Interestingly, loss of other enzymes that reduced dopamine and serotonin levels did not affect tauopathy phenotypes, indicating that changes in dopamine and serotonin precursors, but not dopamine and serotonin themselves, reduce tauopathy. Hypothesis: Dopamine and serotonin precursors or their metabolites reduce tauopathy by activating specific signaling pathways that modulate tau. Proposed Experiments: The C. elegans tauopathy model and an acute slice ex vivo model of tauopathy will be used to 1) determine the molecules that mediate the reduction of tauopathy seen with loss of DOPA decarboxylase 2) identify the signaling pathways that mediate reduction of tauopathy by loss of DOPA decarboxylase 3) validate mechanisms identified in the C. elegans tauopathy model with a mammalian tauopathy model. Expected Outcomes: The proposed studies will result in the identification of novel mechanisms for regulating tauopathy and new therapeutic strategies for treating tauopathies. Future work will evaluate the most promising candidates in whole animal models of tauopathy. Career and Training Goals: My overall career goal is to discover novel therapeutic strategies against neurodegenerative diseases as head of my own independent research group. The CDA2 goals are therefore 1) to establish an experimental pipeline with animal models for discovery of novel therapeutics against tauopathies 2) to gain knowledge and experience in various necessary and relevant skills 3) to establish an independent research laboratory. These goals will be achieved through various training activities under the guidance from my mentorship team.