Identifying the pathogenic mechanisms of swiss-cheese phenotypes to understand neuropathy target esterase associated disorders

Neuropathy Target Esterase (NTE) is an enzyme localized to the ER that regulates Protein Kinase A (PKA) signaling and maintains lipid homeostasis. Exposure to a neurotoxic organophosphate or mutations in NTE cause a spectrum of disorders with neurodegenerative symptoms ranging from blindness, hypogonadism, and cerebellar atrophy to motor neuron loss. Understanding how the functions of NTE are affected by a chemical or mutations and the mechanisms of pathology is important for the identification of pathways and development of therapeutic strategies. Loss of NTE’s ortholog, Swiss-Cheese (SWS), in Drosophila melanogaster causes a dysregulation of PKA signaling, an increase in phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) levels and eventual age-dependent neurodegeneration. The goal of this research was to use Drosophila to understand the etiology of NTE disorders.