Speaker: Sahiba Siddiqui, graduate student in the McGrail Lab

Title: "From pathway dissection to developing genetic tools: A focus on Fyn driven neurodegeneration, Stat3-dependent neuroinflammation, and Caspase conditional alleles"

Abstract: Neurodegenerative diseases Alzheimer’s and Parkinson’s are characterized by progressive loss of specific neuronal populations and the induction of inflammatory responses, resulting in severe cognitive and motor impairments. Understanding the cellular and molecular mechanisms underlying these diseases remains a critical challenge. My dissertation focuses on investigating the role of the Alzheimer’s and Parkinson’s disease risk locus Fyn kinase in neurodegeneration and inflammation. To do so I developed innovative zebrafish models and genetic tools to study the complex interactions between inflammation, mitochondrial dysfunction, and gene regulation in neurodegenerative disease. This work encompassed a number of powerful approaches afforded by zebrafish, including in vivo live microscope imaging of dopaminergic neuron loss, transcriptome analysis to identify novel Fyn effectors, drug treatment to validate novel effector mechanisms, and state of the art CRISPR/Cas9 genome editing. Using our Gal4/UAS zebrafish model of Fyn kinase expressing constitutively active FynY531F in neurons, my analyses revealed Fyn activation led to dopaminergic neuron loss, inflammatory cytokine production and microglia activation. Fyn signaling induced dopaminergic neuron loss via mitochondrial dysfunction was dependent on NF-κB inflammatory signaling, a known target of Fyn kinase. Using transcriptome analysis, I identified Stat3 as a novel downstream effector of Fyn signaling and showed dopaminergic neuron loss and microglia activation were dependent on Stat3 activation by Fyn. Dual inhibitor analysis demonstrated Stat3 and NF-κB pathways synergistically promote Fyn-induced dopaminergic neurodegeneration. To further our understanding of inflammatory signaling in neurodegeneration, I used CRISPR/Cas9 genome editing technology to isolate conditional alleles in the inflammasome activating enzyme Caspase1. The zebrafish Caspase1 alleles will enable future investigation of the cell type specific roles of inflammatory signaling in development and disease. Together, these findings advance our understanding of Fyn kinase's role in neurodegeneration, and provide a new inroad for development of potential therapies to prevent persistent neuroinflammation in neurodegeneration.

Webex link: Request a Webex link by contacting danisej@iastate.edu.