Dobrowolski Steven F, Phua Yu Leng, Sudano Cayla, Spridik Kayla, Zinn Pascal O, Wang Yudong, Bharathi Sivakama, Vockley Jerry, Goetzman Eric
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, United States.
Division of Medical Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, United States.
Mol Genet Metab. 2021 Apr 7. doi: 10.1016/j.ymgme.2021.04.002.
Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). PAH deficiency leads to systemic hyperphenylalaninemia; however, the impact of Phe varies between tissues. To characterize tissue response to hyperphenylalaninemia, metabolomics was applied to tissue from therapy noncompliant classical PKU patients (blood, liver), the Pah classical PKU mouse (blood, liver, brain) and the PAH deficient pig (blood, liver, brain, cerebrospinal fluid). In blood, liver, and CSF from both patients and animal models over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of PKU brain tissue (mouse, pig) evidenced oxidative stress responses and energy dysregulation. In Pah and PKU pig brain tissues, anti-oxidative response by glutathione and homocarnosine is apparent. Oxidative stress in Pah brain was further demonstrated by increased reactive oxygen species. In Pah and PKU pig brain, an increased NADH/NAD ratio suggests a respiratory chain dysfunction. Respirometry in PKU brain mitochondria (mouse, pig) functionally confirmed reduced respiratory chain activity. Glycolysis pathway analytes are over-represented in PKU brain tissue (mouse, pig). PKU pathologies owe to liver metabolic deficiency; yet, PKU liver tissue (mouse, pig, human) shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.
经典型苯丙酮尿症（PKU，OMIM 261600）是由于肝脏中苯丙氨酸羟化酶（PAH）缺乏，该酶可将苯丙氨酸（Phe）酶促转化为酪氨酸（Tyr）。PKU的神经学表型包括脑发育受损、髓鞘形成减少、早发性智力迟钝、癫痫发作以及迟发性特征（神经精神症状、帕金森症）。PAH缺乏导致全身性高苯丙氨酸血症；然而，苯丙氨酸在不同组织中的影响有所不同。为了表征组织对高苯丙氨酸血症的反应，代谢组学被应用于治疗不依从的经典型PKU患者的组织（血液、肝脏）、Pah经典型PKU小鼠（血液、肝脏、脑）以及PAH缺陷猪（血液、肝脏、脑、脑脊液）。在患者和动物模型的血液、肝脏和脑脊液中，过度富集的分析物主要是苯丙氨酸、苯丙氨酸分解代谢物以及与苯丙氨酸相关的分析物（共轭物、含苯丙氨酸的二肽）。除了苯丙氨酸和与苯丙氨酸相关的分析物外，PKU脑组织（小鼠、猪）的代谢组学图谱显示出氧化应激反应和能量失调。在Pah和PKU猪脑组织中，谷胱甘肽和高肌肽的抗氧化反应明显。Pah脑内活性氧的增加进一步证明了氧化应激。在Pah和PKU猪脑中，NADH/NAD比值升高表明呼吸链功能障碍。PKU脑线粒体（小鼠、猪）的呼吸测定在功能上证实了呼吸链活性降低。糖酵解途径分析物在PKU脑组织（小鼠、猪）中过度富集。PKU的病理学归因于肝脏代谢缺陷；然而，PKU肝脏组织（小鼠、猪、人）既未显示能量紊乱也未显示抗氧化反应。PKU脑组织中代谢组学稳态的独特方面以及活性氧增加和呼吸链缺陷为神经疾病机制提供了见解。虽然一些长期以来假定的PKU神经病理学要素得到了代谢组学数据的支持（例如色氨酸和血清素含量降低），但能量失调和组织氧化应激扩展了神经病理学的潜在机制。
