Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration

Katarzyna Siudeja, Balaji Srinivasan, Lanjun Xu, Anil Rana, Jannie de Jong, Ellen A A Nollen, Suzanne Jackowski, Lynn Sanford, Susan Hayflick, Ody C M Sibon

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)755-766
Number of pages12
JournalEMBO Molecular Medicine
Volume3
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Pantothenate Kinase-Associated Neurodegeneration
Coenzyme A
Tubulin
Acetylation
Histones
Drosophila
Proteins
Acetyltransferases
Phenotype
Acetyl Coenzyme A
Histone Deacetylase Inhibitors
Histone Deacetylases
Neurodegenerative Diseases
Lysine
DNA Damage
Maintenance
Survival

Keywords

  • DNA damage
  • HDAC inhibitors
  • NBIA
  • PKAN
  • Protein acetylation

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration. / Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A A; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C M.

In: EMBO Molecular Medicine, Vol. 3, No. 12, 12.2011, p. 755-766.

Research output: Contribution to journalArticle

Siudeja, Katarzyna ; Srinivasan, Balaji ; Xu, Lanjun ; Rana, Anil ; de Jong, Jannie ; Nollen, Ellen A A ; Jackowski, Suzanne ; Sanford, Lynn ; Hayflick, Susan ; Sibon, Ody C M. / Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration. In: EMBO Molecular Medicine. 2011 ; Vol. 3, No. 12. pp. 755-766.
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