Molecular characterisation of DHR38: the Drosophila ortholog of NR4A family of nuclear receptors

• Main Author: Parnaik, Tanvi Rajesh
• Other Authors: Julien Lescar
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences; Nuclear receptor
• Online Access: https://hdl.handle.net/10356/176376
• Institution: Nanyang Technological University

Background: DHR38 is the Drosophila ortholog of the human NR4A family of nuclear receptors (NRs) and is categorized as an orphan NR due to the absence of a classical ligand binding pocket; however, recent agonist discoveries for human NR4A members have challenged this notion, and limited studies exist on the function of DHR38 during the adult stage, despite its significant expression in the brain. Results: Here, I present the first evidence of DHR38’s ligand binding capabilities, by showing Prostaglandin A1 (PGA1) as a potential agonist and transcriptional activator of DHR38, using in vitro binding and luciferase assays. Attempts were made to crystallize DHR38-LBD in complex with PGA1 without success. From a functional perspective, in vivo tissue-specific knockdown of DHR38 in DCC (Dopa- decarboxylase) expressing tissues of Drosophila melanogaster, led to reduced lifespan, locomotor activity, impaired dopaminergic neurons and change in sleep patterns. Molecular analysis revealed altered expression patterns of 10 genes, implicated in dopaminergic, survival, and circadian pathways. Conclusion: PGA1 is an agonist of DHR38, and its knockdown reveals dopaminergic phenotype in Drosophila melanogaster. An in-depth characterisation of DHR38 will expand our understanding of its human orthologs and serve as a model system to identify and screen drug candidates