Elizabeth Sunderhaus, Graduate Student

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Undergraduate education at Cedar Crest College

Lizzy's Project

Investigating the cell type specific roles of Neuropathy Target Esterase in the nervous system and how specific mutations lead to a spectrum of disorders

Neuropathy Target Esterase (NTE) is a phospholipase that maintains lipid homeostasis and can regulate PKA activity. Mutations in NTE in humans have been shown to cause a spectrum of disorders with symptoms ranging from hypogonadism to cerebellar atrophy and blindness. Complete loss of NTE's ortholog, Swiss Cheese (SWS), in Drosophila melanogaster has been shown to cause age-dependent neurodegeneration, including the retina, similar to the degeneration seen in the brain-specific knockouts of mouse NTE when aged. However, SWS and NTE are also expressed in glia, and sws1 has glial defects and cell death. Using a construct with a mutation in the active site of the phospholipase domain of SWS, we found that expression of this construct in glia or neurons cannot rescue degeneration, but it can rescue retinal degeneration when induced in the eye. In contrast, a construct with a mutation in the PKA interaction domain cannot rescue the neuronal degeneration, including photoreceptors, but can rescue glial death. This data shows that different cell types have different requirements for the two functions of SWS, suggesting that disease-associated mutations in NTE specifically affect one of these functions, thereby causing specific phenotypes. To investigate how different mutations in NTE result in distinct phenotypes, we have created transgenic flies expressing wildtype and mutant human NTE (hNTE). Expressing wildtype NTE pan-neuronally in the genetic background of sws1 showed that hNTE can suppress the neurodegeneration and rescue the decreased phototaxis performance and lifespan of the sws1 mutant. Expressing hNTE in glia suppressed cell death, confirming that the human construct can replace SWS, and we can test the functional ability of the mutant constructs in flies. First result show that a hNTE construct without the phospholipase domain due to a frame shift mutation does not rescue degeneration when expressed in neurons, and we are currently testing its function in glia. In addition to the rescue ability, we will also test how the mutant hNTE constructs affect the phospholipase and PKA interaction domains' function. Drosophila can therefore provide a model to gain further insights into the functions of NTE and how specific mutations cause the spectrum of phenotypes seen in patients.

Past Members : 

• Marlene Cassar
• Sudeshna Dutta
• Bonnie Bolkan
• Scott Holbrook
• Jill Wentzell
• Derek Musashe
• Alex Bettencourt da Cruz
• Jakob Tschaepe
• Jennifer Holliday
• Katia Carmine-Simmen
• Mahtab  Niyyati
• Isabell Schwenkert
• Laura Reese
• Thomas Proctor
• Hanil Quirindongo
• Priya Mani
• Mandy Cook