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.

Sahiba Siddiqui

Fang Liu

Anumantha G. Kanthasamy

Maura McGrail

Disease Models & Mechanisms

疾病模型与机制 (DMM) 是一本在线开放获取期刊，专注于使用模型系统更好地理解、诊断和治疗人类疾病。

DMM Disease Models and Mechanisms is an online open-access journal that focuses on using model systems to better understand, diagnose, and treat human diseases.

《DMM Disease Models and Mechanisms》是一本在线开放获取期刊，专注于通过模型系统深入理解、诊断和治疗人类疾病。

Category	Quartile
医学	3
医学, 病理学	2
医学, 细胞生物学	3

Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation

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