• Open Access

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

Authors

  • Katarzyna Siudeja,

    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Balaji Srinivasan,

    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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    • These authors contributed equally to this work.

  • Lanjun Xu,

    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    2. Laboratory of Medical Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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    • These authors contributed equally to this work.

  • Anil Rana,

    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Jannie de Jong,

    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Ellen A. A. Nollen,

    1. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Suzanne Jackowski,

    1. Department of Infectious Diseases St. Jude Children's Research Hospital, Memphis, TN, USA
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  • Lynn Sanford,

    1. Department of Molecular and Medical Genetics, Pediatrics, and Neurology, Oregon Health and Science University, Portland, OR, USA
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  • Susan Hayflick,

    1. Department of Molecular and Medical Genetics, Pediatrics, and Neurology, Oregon Health and Science University, Portland, OR, USA
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  • Ody C. M. Sibon

    Corresponding author
    1. Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    • Tel: +31(0)503632559; Fax: +31(0)503632913

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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.

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