PUBLICATION
Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation
- Authors
- Siddiqui, S., Liu, F., Kanthasamy, A.G., McGrail, M.
- ID
- ZDB-PUB-241206-19
- Date
- 2024
- Source
- Disease models & mechanisms 17(12): (Journal)
- Registered Authors
- McGrail, Maura
- Keywords
- Dopaminergic neuron, Fyn kinase, Microglia activation, Mitophagy, NF-κB, STAT3, TNF-α, Zebrafish neurodegeneration model
- Datasets
- GEO:GSE271955
- MeSH Terms
-
- NF-kappa B*/metabolism
- Inflammation/pathology
- Signal Transduction*
- Dopaminergic Neurons*/metabolism
- Dopaminergic Neurons*/pathology
- Mitochondria/metabolism
- Animals
- Nerve Degeneration*/pathology
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- STAT3 Transcription Factor*/metabolism
- Microglia*/metabolism
- Microglia*/pathology
- Zebrafish*
- Proto-Oncogene Proteins c-fyn*/genetics
- Proto-Oncogene Proteins c-fyn*/metabolism
- PubMed
- 39641161 Full text @ Dis. Model. Mech.
Citation
Siddiqui, S., Liu, F., Kanthasamy, A.G., McGrail, M. (2024) Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation. Disease models & mechanisms. 17(12):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping