Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
Cell Metab. 2019 Jun 4;29(6):1258-1273.e11. doi: 10.1016/j.cmet.2019.03.004. Epub 2019 Mar 28.
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.
亨廷顿病中特定区域神经元毒性的基础尚不清楚。在这里，我们表明，特定区域神经元易损性是星形胶质细胞中底物驱动的反应。HdhQ(150/150)动物的葡萄糖水平较低，每个脑区的星形胶质细胞通过代谢重编程其线粒体来利用内源性、非糖酵解代谢物作为替代燃料来适应。每个区域都有独特的代谢池，星形胶质细胞会相应地进行适应。脆弱的纹状体富含脂肪酸，线粒体通过氧化它们作为能量来源进行重编程，但代价是会加剧活性氧 (ROS) 诱导的损伤。小脑富含氨基酸，这些氨基酸可以通过磷酸戊糖途径或糖异生途径转化为葡萄糖再生的前体。ROS 水平没有升高，这个区域的损伤很小。虽然 mhtt 表达给整个大脑带来了疾病压力，但敏感性或抗性源于适应性应激反应，这种反应本质上是区域特异性的。代谢重编程可能与其他疾病有关。
