Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation

Abstract

AbstractThe 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