939B Poster - 15. Models of human disease
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Unmila Jhuti; Edward Blumenthal

Affiliation: Marquette University, Milwaukee, WI

Keywords:
a. neural degeneration; c. innate immunity

Adult neurodegenerative diseases such as Alzheimer’s and Parkinson’s are one of the main causes of death for elderly population worldwide. Using Drosophila models of neurodegeneration (ND) to study such diseases has been proven useful because they show striking similarities to the human diseases. This project aims to understand ND in flies mutant for drop-dead (drd). Absence of drd expression is associated with adult ND and short lifespan, but the molecular pathways responsible for ND in this model have not been identified. Hyperactivation of innate immunity (HII) has been linked to ND both in human diseases and in Drosophila. It is yet to be identified how HII pathways are activated in adult neurodegenerative diseases. Preliminary data suggest a causal connection of HII with ND in drd mutants. Expression of the antimicrobial peptide genes DptB, CecA1 and AttC was increased by 2-4 fold in drd mutant brains compared to heterozygous sibling controls. Furthermore, drd mutant flies that are heterozygous for mutations in the immune genes rel or imd showed an increased median lifespan (8-10 days) compared to drd mutant controls (4-7 days).
Although ND has been identified in mutant drd brains, the spatiotemporal pattern and pathway(s) of cell death have not been characterized. Immunostaining with the apoptotic marker Dcp-1 suggested activation of caspase-dependent apoptosis in the brains of drd mutants as early as the day of eclosion (P0). Intense and spatially dispersed staining was observed in older (P2-3) flies. Staining with the non-specific cell death marker acridine orange revealed widespread cell death beginning at P0.
Previous work has shown that expression of drd in the respiratory tracheae is necessary and sufficient to prevent ND. Thus, brain cell death could potentially be connected to disruption of gas exchange and hypoxia. However, staining mutant brains with the ROS marker dihydroethidium showed the presence ROS only in older flies (P2-3), but not in younger flies (P0), suggesting that hypoxia is not a primary cause of ND in drd mutants.
Studying the role of drd will provide significant insight into the link between HII and adult ND. Identification of the pathways leading to cell death can help to understand cellular mechanisms potentially responsible for adult neurodegeneration.
Supported by Marquette University and the Northwestern Mutual Data Science Institute.
Keywords: innate immunity, apoptosis, cell death, hypoxia, neurodegeneration.