Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
EMBO Mol Med. 2011 Dec;3(12):755-66. doi: 10.1002/emmm.201100180. Epub 2011 Oct 14.
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.
泛酸激酶相关神经退行性变（PKAN）是一种神经退行性疾病，其病理生理学尚未得到解决。此前，我们在 PKAN 的果蝇模型中观察到辅酶 A 水平降低。辅酶 A 是乙酰辅酶 A 合成所必需的，后者的酰基基团被转移到蛋白质的赖氨酸残基上，该反应受乙酰转移酶调节。乙酰转移酶及其拮抗物组蛋白去乙酰化酶之间的紧密平衡是蛋白质乙酰化状态的一个众所周知的决定因素。然而，辅酶 A 水平对蛋白质乙酰化的影响尚不清楚。在这里，我们研究了中央代谢物辅酶 A 水平的降低是否会诱导蛋白质乙酰化的改变，以及这种改变是否与 PKAN 模型的特定表型相关。我们表明，在各种生物体中，适当的辅酶 A 代谢对于维持组蛋白和微管蛋白乙酰化是必需的，这些蛋白质的乙酰化降低与 DNA 损伤反应受损、运动功能下降和存活能力下降有关。泛酸和 HDAC 抑制剂部分挽救了蛋白质乙酰化的降低和并发表型，这表明了未来 PKAN 治疗开发的可能方向。
