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, or cell eating. Phagocytosis consists of the recognition, internalization, and degradation of external material. 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.
To untangle the links between glial phagocytosis and neurodegeneration, we used the fruit fly Drosophila melanogaster, whose complex nervous system harbors phagocytic glia analogous to those in humans. We analyzed mutant flies lacking the phagocytic receptor Draper and found that they show an accumulation of neuronal cell corpses, which result from developmental programmed cell death and persist throughout the organism’s life. We also found that 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. This hypothesis stems from the findings that persisting cell corpses in other tissues cause inflammation, and that neuroinflammation is thought to worsen 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.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44106 |
| Date | 30 March 2022 |
| Creators | Elguero, Johnny Emma |
| Contributors | McCall, Kimberly |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
Page generated in 0.0023 seconds