Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 15; pp. 6988 - 6993
• Main Authors: Rana, Anil, Seinen, Erwin, Siudeja, Katarzyna, Muntendam, Remco, Srinivasan, Balaji, van der Want, Johannes J, Hayflick, Susan, Reijngoud, Dirk-Jan, Kayser, Oliver, Sibon, Ody C.M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.04.2010; National Acad Sciences
• Subjects: animal disease models; Animals; Biological Sciences; Biosynthesis; brain; Brain - pathology; Brain diseases; cell respiration; coenzyme A; Coenzyme A - chemistry; Coenzymes; Drosophila; Drosophila - genetics; Drosophila - metabolism; Drosophila melanogaster; Enzymes; Gene Expression Regulation; Genotype & phenotype; Humans; insect proteins; Kinases; Lead; Life span; locomotion; longevity; Mitochondria; Mitochondria - metabolism; Models, Biological; Mutation; nervous system diseases; Neurodegeneration; Neurodegenerative diseases; oxidation; Oxidative Stress; Oxygen - chemistry; Pantetheine - analogs & derivatives; Pantetheine - pharmacology; panthothenate kinase; pantothenate kinase-associated neurodegeneration; Pantothenate Kinase-Associated Neurodegeneration - drug therapy; Phenotype; Phenotypes; Phosphotransferases (Alcohol Group Acceptor) - metabolism; phosphotransferases (kinases); Small interfering RNA
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0912105107

Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.