The Alzheimer’s Disease and Parkinson’s Disease risk locus Fyn kinase is implicated in neurodegeneration and inflammatory signaling. To investigatein vivomechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Usingin vivolive imaging we demonstrate neural FynY531F expression lead to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction oftnfa,il1b, andil12ainflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn driven dopaminergic neuron loss and the inflammatory response were dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.Summary StatementThis study describes a novelin vivomodel of neural Fyn Kinase activation and identifies Stat3 signaling as a downstream Fyn effector in dopaminergic neuron degeneration and neuroinflammation.Abstract FigureGraphical abstract- Neural Fyn signaling drives dopaminergic neurodegeneration, mitochondria accumulation, and microglia activation- Fyn driven neurodegeneration and cytokine expression are dependent on Stat3- Stat3 and NF-kB pathways synergize in dopaminergic neuron degeneration