Chen Xi, Xie Chengsong, Sun Lixin, Ding Jinhui, Cai Huaibin
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, United States of America.
Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, United States of America.
PLoS One. 2015 Aug 28;10(8):e0136612. doi: 10.1371/journal.pone.0136612. eCollection 2015.
Metabolic homeostasis is critical for all biological processes in the brain. The metabolites are considered the best indicators of cell states and their rapid fluxes are extremely sensitive to cellular changes. While there are a few studies on the metabolomics of Parkinson's disease, it lacks longitudinal studies of the brain metabolic pathways affected by aging and the disease. Using ultra-high performance liquid chromatography and tandem mass spectroscopy (UPLC/MS), we generated the metabolomics profiling data from the brains of young and aged male PD-related α-synuclein A53T transgenic mice as well as the age- and gender-matched non-transgenic (nTg) controls. Principal component and unsupervised hierarchical clustering analyses identified distinctive metabolites influenced by aging and the A53T mutation. The following metabolite set enrichment classification revealed the alanine metabolism, redox and acetyl-CoA biosynthesis pathways were substantially disturbed in the aged mouse brains regardless of the genotypes, suggesting that aging plays a more prominent role in the alterations of brain metabolism. Further examination showed that the interaction effect of aging and genotype only disturbed the guanosine levels. The young A53T mice exhibited lower levels of guanosine compared to the age-matched nTg controls. The guanosine levels remained constant between the young and aged nTg mice, whereas the aged A53T mice showed substantially increased guanosine levels compared to the young mutant ones. In light of the neuroprotective function of guanosine, our findings suggest that the increase of guanosine metabolism in aged A53T mice likely represents a protective mechanism against neurodegeneration, while monitoring guanosine levels could be applicable to the early diagnosis of the disease.
代谢稳态对大脑中的所有生物过程至关重要。代谢物被认为是细胞状态的最佳指标，其快速通量对细胞变化极为敏感。虽然有一些关于帕金森病代谢组学的研究，但缺乏对受衰老和疾病影响的脑代谢途径的纵向研究。我们使用超高效液相色谱和串联质谱（UPLC/MS），从年轻和老年雄性帕金森病相关α-突触核蛋白A53T转基因小鼠以及年龄和性别匹配的非转基因（nTg）对照小鼠的大脑中生成了代谢组学分析数据。主成分分析和无监督层次聚类分析确定了受衰老和A53T突变影响的独特代谢物。随后的代谢物集富集分类显示，无论基因型如何，老年小鼠大脑中的丙氨酸代谢、氧化还原和乙酰辅酶A生物合成途径都受到了严重干扰，这表明衰老在脑代谢改变中起更突出的作用。进一步检查表明，衰老和基因型的相互作用仅干扰了鸟苷水平。与年龄匹配的nTg对照相比，年轻的A53T小鼠鸟苷水平较低。年轻和老年nTg小鼠之间的鸟苷水平保持恒定，而老年A53T小鼠与年轻突变小鼠相比，鸟苷水平大幅增加。鉴于鸟苷的神经保护功能，我们的研究结果表明，老年A53T小鼠中鸟苷代谢的增加可能代表了一种针对神经退行性变的保护机制，而监测鸟苷水平可能适用于该疾病的早期诊断。
