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

> **NIH NIH FI2** · U.S. NATIONAL INST/NEURO/DS/STROKE · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10024527
- **Project number:** 1FI2GM138078-01
- **Recipient organization:** U.S. NATIONAL INST/NEURO/DS/STROKE
- **Principal Investigator:** Andrew Moehlman
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024527

## Citation

> US National Institutes of Health, RePORTER application 10024527, Understanding the role of innate immunity and Sting-mediated inflammation in models of Parkinsons's Disease in Drosophila melanogaster (1FI2GM138078-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10024527. Licensed CC0.

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