Exploring novel strategies to rescue Coenzyme A deficiency-related diseases in Drosophila melanogaster models

Coenzyme A (CoA) is a crucial molecule for many cellular metabolic pathways in all organisms including humans. The canonical biosynthesis of CoA constitutes five enzymatic steps from the substrate pantothenate. These five enzymes, in the order of each subsequent catalyzed step, are pantothenate kinase (PANK), phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), phosphopantetheine adenylyltransferase (PPAT), and dephospho-CoA kinase (DPCK). In eukaryotes like fruit flies, mice, and humans, PPAT and DPCK are combined to one enzyme called COASY. Mutations in PANK2, PPCS, and COASY cause three different human diseases. This thesis uses fruitfly models to explore the pathophysiological characteristics of CoA biosynthesis deficiency-related diseases, and aims to identify potential treatment strategies to cure or relieve these diseases. We studied several fruit fly models and were able to link four neurodegenerative diseases to the CoA-mtACP-PDH pathway. In addition, 2 alternative routes to acquire CoA were identified. The first route includes maternal contribution of CoA and its precursors. The second route identified bacterially-mediated conversion of pantethine to a CoA intermediate by symbiotic microbiome species. These findings add to our knowledge regarding the pathophysiology of CoA biosynthesis-related diseases and shed light on potential cures or amelioration of disease symptoms.