Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration.
Bottom Line: Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN.Here we investigate whether decreased levels of the central metabolite Coenzyme A induce alterations in protein acetylation and whether this correlates with specific phenotypes of PKAN models.We show that in various organisms proper Coenzyme A metabolism is required for maintenance of histone- and tubulin acetylation, and decreased acetylation of these proteins is associated with an impaired DNA damage response, decreased locomotor function and decreased survival.
Affiliation: Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Show MeSH
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Mentions: Although in Drosophila, similar to other species, tubulin undergoes acetylation at the lysine 40 residue, the physiological importance of this modification in flies or Drosophila cell lines has not been demonstrated. On the contrary, in C. elegans reduced acetylation of tubulin has been recently linked with an impaired touch response (Shida et al, 2010). To investigate whether the link between CoA metabolism and tubulin acetylation is evolutionarily conserved, we first tested if impaired function of PANK coincides with reduced acetylation levels of tubulin in C. elegans as well, using a C. elegans mutant carrying a deletion of 773 bp within the pnk-1 gene, an ortholog of human PANK2 (Zhou et al, 2001, Fig S3 of Supporting information and methods of Supporting information). As revealed by Western blot analysis, the pnk-1 mutant animals showed decreased levels of acetylated tubulin, which could be rescued, similarly to the Drosophila model, with the addition of pantethine to the food (Fig 3A). In agreement with the reported link between tubulin acetylation and the function of touch receptor neurons in C. elegans, pnk-1 mutant worms showed a decreased touch response, which was also rescued by pantethine feeding (Fig 3B). Together these data strongly indicate a conserved link between CoA metabolism and tubulin acetylation.
Affiliation: Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.