Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation.
| Autor: | Siddiqui S; Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA.; Interdepartmental Genetics and Genomics Graduate Program (IGG), Iowa State University, Ames, IA 50011, USA., Liu F; Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA., Kanthasamy AG; Center for Brain Science and Neurodegenerative Diseases, Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602, USA., McGrail M; Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA.; Interdepartmental Genetics and Genomics Graduate Program (IGG), Iowa State University, Ames, IA 50011, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Disease models & mechanisms [Dis Model Mech] 2024 Dec 01; Vol. 17 (12). Date of Electronic Publication: 2024 Dec 06. |
| DOI: | 10.1242/dmm.052011 |
| Abstrakt: | The Alzheimer's disease and Parkinson's 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 demonstrated that neural FynY531F expression leads 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 was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that 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. Competing Interests: Competing interests M.M. has competing interests with Recombinetics Inc., Immusoft Inc., LifEngine and LifEngine Animal Health. (© 2024. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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