243B Poster - 02. Immunity and the microbiome
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Guangmei Liu ¹; Johnny Elguero ¹; Katie Tiemeyer ¹; Heena Gandevia ¹; Iker Etchegaray ¹; Mel Feany ²; Kim McCall ¹

Affiliations:
1) Department of Biology, Boston University, Boston, MA; 2) Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA

Keywords:
c. innate immunity; k. glia

In nervous system development, as well as in disease and injury, neurons die through programmed cell death, leaving behind cell corpses which must be removed. The clearance of these corpses is accomplished through phagocytosis. In the nervous system, glial cells act as phagocytes, engulfing dead neurons and debris to ensure proper morphology and tissue homeostasis. Glial phagocytosis has been implicated in several neurological diseases. In humans, increased numbers of phagocytic glia are observed in conditions like Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. In vitro, glia have been shown to clear protein aggregates like those found in neurodegenerative disease. Moreover, variants of genes implicated in glial phagocytosis have been identified as risk factors for neurodegenerative diseases. However, how phagocytosis defects might cause or worsen neurodegeneration remains unknown. We are using the Drosophila melanogaster, whose complex nervous system harbors phagocytic glia analogous to those in humans, to tackle this question. Our lab previously found that mutant flies lacking the phagocytic receptor Draper show an accumulation of neuronal cell corpses, which result from developmental programmed cell death and persist throughout the organism’s life. And flies lacking glial Draper display age-dependent neurodegeneration.
To determine how phagocytic defects lead to neurodegeneration in the draper mutant, we investigated the hypothesis that persisting cell corpses in the brain lead to chronic increased immunity, resulting in neurodegeneration. We measured activation of the immune pathway Imd in aging draper mutants and found that the antimicrobial peptide attacin A is highly overexpressed in fat body. We then suppressed the Imd pathway by knocking down Relish in glia and fat body in draper mutants and found that neurodegeneration was reduced, indicating that immune activation promotes the neurodegeneration in draper mutants. Taken together, these findings indicate that phagocytic defects lead to or exacerbate neurodegeneration through increased immune signaling, both systemically and in the brain.
To define the causality of neurodegeneration in draper mutants, we are testing two hypotheses that the neurodegenerative phenotype results from persisting corpses or from defective phagocytic function of glia. We are comparing the severity of neurodegeneration in aging flies with either only persisting corpses or only defective phagocytic function. To further define the consequences of neurodegeneration caused by knocking down draper in fly glia, we are charactering the cellular identities of dead neurons in these aging flies and examining related behavioral deficits such as locomotion activity and learning and memory function.