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bioRxiv · 10.1101/2024.07.05.602238

Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation

Siddiqui, S.·Liu, F.·Kanthasamy, A. G.·McGrail, M.
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Abstract

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

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Siddiqui, S., Liu, F., Kanthasamy, A. G., McGrail, M.. 2024-07-09. Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation. https://doi.org/10.1101/2024.07.05.602238

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