4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.,EMBO Molecular Medicine

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4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-10-29 , DOI: 10.15252/emmm.201910489
Suh Young Jeong ₁ , Penelope Hogarth _{1,

2} , Andrew Placzek ₃ , Allison M Gregory ₁ , Rachel Fox ₁ , Dolly Zhen ₁ , Jeffrey Hamada ₁ , Marianne van der Zwaag ₄ , Roald Lambrechts ₄ , Haihong Jin ₃ , Aaron Nilsen ₃ , Jared Cobb ₅ , Thao Pham ₅ , Nora Gray ₂ , Martina Ralle ₁ , Megan Duffy ₁ , Leila Schwanemann ₁ , Puneet Rai ₁ , Alison Freed ₁ , Katrina Wakeman ₁ , Randall L Woltjer ₅ , Ody Cm Sibon ₄ , Susan J Hayflick _{1,

2,

6}

Affiliation

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4'-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4'-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4'-phosphopantetheine as a candidate therapeutic for PKAN.

中文翻译：

4'-磷酸泛茶碱可纠正 PKAN 哺乳动物模型中的 CoA、铁和多巴胺代谢缺陷。

泛酸激酶相关神经变性 (PKAN) 是 CoA 代谢的先天性错误，导致肌张力障碍、帕金森病和脑铁积累。缺乏良好的哺乳动物模型阻碍了发病机制的研究和合理治疗方法的开发。我们采用了一种新方法来研究现有的 Pank2 小鼠突变体，发现分离易受疾病影响的大脑揭示了 CoA 代谢、铁稳态和多巴胺代谢的区域扰动以及复合物 I 和丙酮酸脱氢酶的功能缺陷。给小鼠喂食 CoA 途径中间体 4'-磷酸泛酰乙胺、CoA、铁和多巴胺相关生物标志物的标准化水平以及线粒体酶的活性。 4'-磷酸泛酰乙胺也能恢复人类细胞的变化。我们可以通过线粒体酰基载体蛋白的激活，从机制上将 CoA 代谢缺陷与这些次级效应联系起来，线粒体酰基载体蛋白对于氧化磷酸化、铁硫簇生物合成和线粒体脂肪酸合成至关重要。我们证明了我们的模型在概括人类疾病特征方面的保真度。此外，我们还确定了药效生物标志物，提供了对疾病发病机制的见解，并为 4'-磷酸泛酰乙胺作为 PKAN 的候选治疗剂提供了证据。

更新日期：2019-12-06

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