Pantothenate kinase (PanK) is the first enzyme in the coenzyme A (CoA) biosynthetic pathway. The differential expression of the four-active mammalian PanK isoforms regulates CoA levels in different tissues and PANK2 mutations lead to Pantothenate Kinase Associated Neurodegeneration (PKAN). The molecular mechanisms that potentially underlie PKAN pathophysiology are investigated in a mouse model of CoA deficiency in the central nervous system (CNS). Both PanK1 and PanK2 contribute to brain CoA levels in mice and so a mouse model with a systemic deletion of Pank1 together with neuronal deletion of Pank2 was generated. Neuronal Pank2 expression in double knockout mice decreased starting at P9-11 triggering a significant brain CoA deficiency. The depressed brain CoA in the mice correlates with abnormal forelimb flexing and weakness that, in turn, contributes to reduced locomotion and abnormal gait. Biochemical analysis reveals a reduction in short-chain acyl-CoAs, including acetyl-CoA and succinyl-CoA. Comparative gene expression analysis reveals that the CoA deficiency in brain is associated with a large elevation of Hif3a transcript expression and significant reduction of gene transcripts in heme and hemoglobin synthesis. Reduction of brain heme levels is associated with the CoA deficiency. The data suggest a response to oxygen/glucose deprivation and indicate a disruption of oxidative metabolism arising from a CoA deficiency in the CNS.

中文翻译：

---

泛酸激酶缺陷型小鼠模型揭示了与脑辅酶减少相关的基因表达程序。

泛酸激酶（PanK）是辅酶A（CoA）生物合成途径中的第一个酶。四种活性哺乳动物PanK亚型的差异表达调节不同组织中的CoA水平，PANK2突变导致泛酸激酶相关的神经变性（PKAN）。在中枢神经系统（CNS）的CoA缺乏症小鼠模型中研究了可能是PKAN病理生理基础的分子机制。PanK1和PanK2均对小鼠的大脑CoA水平有贡献，因此生成了具有Pank1系统性缺失和Pank2神经元缺失的小鼠模型。从P9-11开始，双基因敲除小鼠的神经元Pank2表达下降，从而引发严重的脑CoA缺乏症。小鼠大脑CoA的降低与前肢弯曲和肌无力有关，反过来，有助于减少运动和异常步态。生化分析表明，短链酰基辅酶A减少了，包括乙酰辅酶A和琥珀酰辅酶A。比较基因表达分析表明，大脑中的CoA缺乏与Hif3a转录物表达的大幅升高以及血红素和血红蛋白合成中基因转录物的显着减少有关。脑血红素水平的降低与CoA缺乏症有关。数据表明对氧/葡萄糖剥夺有反应，并表明中枢神经系统中CoA缺乏引起的氧化代谢破坏。比较基因表达分析表明，大脑中的CoA缺乏与Hif3a转录物表达的大幅升高以及血红素和血红蛋白合成中基因转录物的显着减少有关。脑血红素水平的降低与CoA缺乏症有关。数据表明对氧/葡萄糖剥夺有反应，并表明中枢神经系统中CoA缺乏引起的氧化代谢破坏。比较基因表达分析表明，大脑中的CoA缺乏与Hif3a转录物表达的大幅升高以及血红素和血红蛋白合成中基因转录物的显着减少有关。脑血红素水平的降低与CoA缺乏症有关。数据表明对氧/葡萄糖剥夺有反应，并表明中枢神经系统中CoA缺乏引起的氧化代谢破坏。