Sbodio Juan I, Snyder Solomon H, Paul Bindu D
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8843-8. doi: 10.1073/pnas.1608264113. Epub 2016 Jul 19.
Disturbances in amino acid metabolism, which have been observed in Huntington's disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.
在亨廷顿舞蹈症（HD）中观察到的氨基酸代谢紊乱，可能是HD患者严重消瘦的原因。HD由亨廷顿蛋白（Htt）中多聚谷氨酰胺重复序列的扩增引发，影响从转录调控到认知和运动功能等多种细胞过程。我们在此表明，由于异常的半胱氨酸生物合成和转运导致的氧化应激，氨基酸稳态的主要调节因子——激活转录因子4（ATF4）在HD中功能失调。与这些观察结果一致，补充抗氧化剂可逆转ATF4对营养应激的紊乱反应。我们的研究结果建立了氨基酸代谢与导致细胞毒性的氧化应激之间的分子联系。这种信号级联可能与其他涉及氧化还原失衡和氨基酸代谢缺陷的疾病有关。
