Understanding the role of innate immunity and Sting-mediated inflammation in models of Parkinsons's Disease in Drosophila melanogaster

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Project Summary Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, controversy remains whether inflammation suppresses or exacerbates disease pathology. It was recently demonstrated that alleviation of interferon (IFN) signaling in mice, through elimination of the cGas/STING pathway, prevented neurodegeneration models of Parkinson’s Disease in PARK-/- and PINK1-/- backgrounds, with mice harboring an error-prone mitochondria DNA polymerase (PolG-mutator). It remains unknown how the immunity signaling regulated by STING (Stimulator of Interferon Genes) is contributing to loss of the dopaminergic neurons. This PD-induced neuronal death can be modeled in the genetically traceable and rapidly reproducing model organism Drosophila melanogaster, which has a well-characterized innate immune response. I hypothesize that innate immune response pathways conserved from flies to humans, such as the NF-kB and JAK/STAT pathways are activated in response to genetic and pathological inhibition of mitochondria quality control pathways. In my research training plan, I propose to test the combined effects of mitochondria DNA mutation accumulation with infection-triggered immune signaling on dopaminergic neuron degeneration in multiple genetic models of Parkinson’s Disease. Further, I intend to test suppressors of neuronal cell death in this double hit model of impaired mitophagy and infection to identify potentially novel mediators of neuronal death. The proposed research also aims to characterize the divergent mechanism of cytosolic nucleotide sensing by Sting in the fruit fly, which lack the canonical upstream activator cGas. Identification of the source of the cyclic nucleotides which activate Sting will greatly enhance our understand of the evolutionary history of innate immune pathways and could lead to the discovery of novel components in the sensing of cytosolic DNA, both from foreign sources such as viruses or bacteria and endogenous DNA released from damaged mitochondria or nuclei. This fellowship training plan provides novel intellectual challenges, opportunities for scientific skill training and professional growth, and concrete designs for career development and job searching. The proposed research and training plan will provide the applicant with the necessary skillsets to succeed in the challenging academic research environment.