Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration

Anil Rana, Erwin Seinen, Katarzyna Siudeja, Remco Muntendam, Balaji Srinivasan, Johannes J. Van Der Want, Susan Hayflick, Dirk Jan Reijngoud, Oliver Kayser, Ody C.M. Sibon

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6988-6993
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number15
DOIs
StatePublished - Apr 13 2010

Keywords

  • Coenzyme A
  • Lifespan
  • Mitochondria
  • Oxidative stress
  • PKAN

ASJC Scopus subject areas

  • General

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    Rana, A., Seinen, E., Siudeja, K., Muntendam, R., Srinivasan, B., Van Der Want, J. J., Hayflick, S., Reijngoud, D. J., Kayser, O., & Sibon, O. C. M. (2010). Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 6988-6993. https://doi.org/10.1073/pnas.0912105107