Department of Neonatology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Pharmacy, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School & Hospital of Stomatology, Tongji University, Shanghai, China.
CNS Neurosci Ther. 2020 Apr;26(4):486-493. doi: 10.1111/cns.13214. Epub 2019 Aug 31.
Phenylketonuria (PKU), which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, is one of the most common inherited diseases of amino acid metabolism. Phenylketonuria is characterized by an abnormal accumulation of phenylalanine and its metabolites in body fluids and brain tissues, subsequently leading to severe brain dysfunction. Various pathophysiological and molecular mechanisms underlying brain dysfunction in PKU have been described. However, the metabolic changes and their impacts on the function of cerebral cortices of patients with PKU remain largely unknown.
We measured the levels of small molecule metabolites in the cerebrocortical tissues of PKU mice and wild-type control mice using liquid chromatography-mass spectrometry (LC-MS)-based metabolome analysis. Differential metabolites were further subjected to metabolic pathway and enrichment analysis.
Metabolome analysis revealed 35 compounds among 143 detected metabolites were significantly changed in PKU mice as compared to those in their wild-type littermates. Metabolic pathway and enrichment analysis of these differential metabolites showed that multiple metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine biosynthesis; alanine, aspartate, and glutamate metabolism; purine metabolism; arginine and proline metabolism and methionine metabolism, were impacted in the cerebral cortices of PKU mice.
The data revealed that multiple metabolic pathways in cerebral cortices of PKU mice were disturbed, suggesting that the disturbances of the metabolic pathways might contribute to neurological or neurodevelopmental dysfunction in PKU, which could thus provide new insights into brain pathogenic mechanisms in PKU as well as mechanistic insights for better understanding the complexity of the metabolic mechanisms of the brain dysfunction in PKU.
苯丙酮尿症（PKU）是由苯丙氨酸羟化酶（PAH）基因突变引起的最常见的氨基酸代谢遗传疾病之一。PKU 的特征是体液和脑组织中苯丙氨酸及其代谢物的异常积累，随后导致严重的脑功能障碍。已经描述了 PKU 中脑功能障碍的各种病理生理和分子机制。然而，PKU 患者大脑代谢变化及其对大脑皮质功能的影响在很大程度上仍不清楚。
我们使用基于液相色谱-质谱（LC-MS）的代谢组学分析测量了 PKU 小鼠和野生型对照小鼠大脑皮质组织中小分子代谢物的水平。进一步对差异代谢物进行代谢途径和富集分析。
代谢组学分析显示，与野生型同窝仔相比，PKU 小鼠中 143 种检测到的代谢物中有 35 种化合物明显改变。对这些差异代谢物的代谢途径和富集分析表明，包括苯丙氨酸、酪氨酸和色氨酸生物合成；缬氨酸、亮氨酸和异亮氨酸生物合成；丙氨酸、天冬氨酸和谷氨酸代谢；嘌呤代谢；精氨酸和脯氨酸代谢以及蛋氨酸代谢在内的多个代谢途径在 PKU 小鼠的大脑皮质中受到影响。
这些数据表明，PKU 小鼠大脑皮质中的多个代谢途径受到干扰，提示代谢途径的紊乱可能导致 PKU 中的神经或神经发育功能障碍，从而为 PKU 的脑发病机制提供新的见解，并为更好地理解 PKU 中大脑功能障碍的代谢机制的复杂性提供机制见解。
