title: Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration.
abstract: Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-known determining factor for the acetylation status of proteins. However, the influence of Coenzyme A levels on protein acetylation is unknown. 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. Decreased protein acetylation and the concurrent phenotypes are partly rescued by pantethine and HDAC inhibitors, suggesting possible directions for future PKAN therapy development.
authors: Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Katarzyna
authors: K
authors: Siudeja
authors: Balaji
authors: B
authors: Srinivasan
authors: Lanjun
authors: L
authors: Xu
authors: Anil
authors: A
authors: Rana
authors: Jannie
authors: J
authors: de Jong
authors: Ellen A A
authors: EA
authors: Nollen
authors: Suzanne
authors: S
authors: Jackowski
authors: Lynn
authors: L
authors: Sanford
authors: Susan
authors: S
authors: Hayflick
authors: Ody C M
authors: OC
authors: Sibon
mesh_terms: D000107:Acetylation; D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010204:Pantetheine / Q000031:analogs & derivatives / Q000378:metabolism; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000503:physiopathology*; D011499:Protein Processing, Post-Translational; D014404:Tubulin / Q000378:metabolism*
chemical_list: D006657:Histones; D014404:Tubulin; D010204:Pantetheine; C005425:pantethine; D003065:Coenzyme A