Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation

The Alzheimers Disease and Parkinsons Disease risk locus Fyn kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live 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 of tnfa, il1b, and il12a inflammatory 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-{kappa}B pathways. Dual chemical inhibition demonstrated Stat3 acts synergistically with NF-{kappa}B 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 novel in vivo model of neural Fyn Kinase activation and identifies Stat3 signaling as a downstream Fyn effector in dopaminergic neuron degeneration and neuroinflammation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/602238v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d783a4org.highwire.dtl.DTLVardef@3b838org.highwire.dtl.DTLVardef@33790eorg.highwire.dtl.DTLVardef@1508c64_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO - 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 C_FIG