Study Rationale:
Parkinson’s Disease (PD) is characterized by neuronal aggregation of toxic alpha-synuclein (aS) protein and subsequent loss of neurons. My research found that neurons with aS aggregates develop DNA damage that activate the DNA sensing “alarm” system called cGAS-STING. Previously it was thought that this only occurs in immune cells of brain, but I have found, in both preclinical and human brain, that cGAS-STING activation occurs in diseased neurons with aS clumps. The main goal of this research is to use human neurons to determine if aS pathology causes DNA damage and activates cGAS-STING in neurons and whether cGAS-STING mediates toxicity of aS pathology.
Hypothesis:
My hypothesis is that in PD, toxic neuronal aggregates of aS protein cause DNA damage and activates cGAS-STING pathway in neuronal cell-type specific way. I also hypothesize that neuronal cGAS-STING activation not only triggers inflammatory activation but also directly contributes to the demise of human dopaminergic neurons with aS pathology.
Study Design:
I will use preclinical models and human tissues to fully define relationship between neuronal aS aggregates, DNA damage, and cGAS-STING activation. I will also use inducible pluripotent stem cells (iPSC) differentiated into neurons and engineered to develop toxic aS aggregates. I will look for markers of DNA damage, activation of cGAS-STING pathway and subsequent inflammation in neurons. We will also compare the effects in neurotransmitter dopamine producing neurons which are more vulnerable in PD to other types of neurons. Using gene deletion or targeted drugs, we will test whether by blocking this pathway will eventually protect the neurons from further damage and death and slow down disease progression.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Investigating neuronal cGAS-STING activation will address a fundamental gap in PD pathogenesis. It will uncover a novel mechanism linking inflammation to neurons. I hope to identify potential early biomarkers of disease progression and a promising therapeutic target to protect loss of neurons.
Next Steps for Development:
The next steps will be to determine how neuronal aS pathology causes DNA damage and/or cGAS-STING activation (e.g. Lysosomal or Endoplasmic Reticulum dysfunction), validate this pathway using in-vivo models, and test therapies that target this pathway. This study will pave the way for targeted therapies that slow down disease progression.