De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system

• Published in: Human molecular genetics Vol. 17; no. 13; pp. 2058 - 2069
• Main Authors: Bosveld, Floris, Rana, Anil, van der Wouden, Petra E., Lemstra, Willy, Ritsema, Martha, Kampinga, Harm H., Sibon, Ody C. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2008; Oxford Publishing Limited (England); Oxford University Press (OUP)
• Subjects: Animals; Biological and medical sciences; Biosynthetic Pathways; Catalase - genetics; Catalase - metabolism; Cell Survival; Central Nervous System - enzymology; Central Nervous System - growth & development; Coenzyme A - biosynthesis; Coenzyme A - genetics; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA - genetics; Drosophila melanogaster; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Evolution, Molecular; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Life Sciences; Male; Molecular and cellular biology; Motor Activity; Mutation; Peptide Synthases - genetics; Peptide Synthases - metabolism; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Rats; Reactive Oxygen Species - pharmacology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Thioredoxin-Disulfide Reductase - genetics; Thioredoxin-Disulfide Reductase - metabolism; Arthropoda; Insecta; DNA; Development; Genetics; Nervous system; Biosynthesis; Invertebrata; Drosophila melanogaster; Diptera; De novo; Drosophilidae
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddn105

In a forward genetic screen in Drosophila melanogaster, aimed to identify genes required for normal locomotor function, we isolated dPPCS (the second enzyme of the Coenzyme A biosynthesis pathway). The entire Drosophila CoA synthesis route was dissected, annotated and additional CoA mutants were obtained (dPANK/fumble) or generated (dPPAT-DPCK). Drosophila CoA mutants suffer from neurodegeneration, altered lipid homeostasis and the larval brains display increased apoptosis. Also, de novo CoA biosynthesis is required to maintain DNA integrity during the development of the central nervous system. In humans, mutations in the PANK2 gene, the first enzyme in the CoA synthesis route, are associated with pantothenate kinase-associated neurodegeneration. Currently, the pathogenesis of this neurodegenerative disease is poorly understood. We provide the first comprehensive analysis of the physiological implications of mutations in the entire CoA biosynthesis route in an animal model system. Surprisingly, our findings reveal a major role of this conserved pathway in maintaining DNA and cellular integrity, explaining how impaired CoA synthesis during CNS development can elicit a neurodegenerative phenotype.