美国劳伦斯伯克利国家实验室分子生物物理学与综合生物成像部门的Cynthia T. McMurray研究小组，揭示了通过星形胶质细胞的代谢重编程可在亨廷顿舞蹈病小鼠模型中区分区域特异性神经元的易感性。 2019年6月，这一研究成果发表在国际知名学术期刊《Cell Metabolism》杂志上。

本项研究中，课题组成员发现，区域特异性神经元易损性是星形胶质细胞中由基质驱动的反应。在葡萄糖含量较低的HdhQ(150/150)动物模型中，每个大脑区域的星形胶质细胞都能够通过其代谢重组的线粒体, 利用内源性非糖酵解代谢物作为替代燃料, 从而适应内环境。 每个区域都有不同的代谢特征，星形胶质细胞都能够相应地适应。易受攻击的纹状体富含脂肪酸，线粒体通过脂肪酸氧化作为能量来源进行重新编程，随之而来的是不断升级的活性氧生成过量诱导的生物分子氧化损伤。小脑组织富含氨基酸，它们葡萄糖分子通过戊糖磷酸途径或糖异生途径再生的前体。由于活性氧含量没有升高，因此这个区域几乎没有受到损害。 当突变亨廷顿蛋白（mhtt）的表达给整个大脑带来疾病压力时，固有区域特异性做出适应压力性反馈，表现为适应性敏感或产生抵抗力。

此前，对于亨廷顿舞蹈病中区域特异性神经毒性的发生机制尚不清楚。

附：英文原文

Title: Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

Author: Aris A. Polyzos, Do Yup Lee, Rupsa Datta, Ke Xu, Enrico Gratton, Cynthia T. McMurray

Issue&Volume:Jun 04, 2019 Volume 29Issue 6

Abstract: The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ( 150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.

DOI: https://doi.org/10.1016/j.cmet.2019.03.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30132-9