Celltec-UB, Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain.
Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
EMBO J. 2018 May 2;37(9). doi: 10.15252/embj.201797368. Epub 2018 Apr 3.
The formation of neurites is an important process affecting the cognitive abilities of an organism. Neurite growth requires the addition of new membranes, but the metabolic remodeling necessary to supply lipids for membrane expansion is poorly understood. Here, we show that synaptic activity, one of the most important inducers of neurite growth, transcriptionally regulates the expression of neuronal glucose transporter Glut3 and rate-limiting enzymes of glycolysis, resulting in enhanced glucose uptake and metabolism that is partly used for lipid synthesis. Mechanistically, CREB regulates the expression of Glut3 and Siah2, the latter and LDH activity promoting the normoxic stabilization of HIF-1α that regulates the expression of rate-limiting genes of glycolysis. The expression of dominant-negative HIF-1α or Glut3 knockdown blocks activity-dependent neurite growth while pharmacological inhibition of the glycolysis and specific ablation of HIF-1α in early postnatal mice impairs the neurite architecture. These results suggest that the manipulation of neuronal glucose metabolism could be used to treat some brain developmental disorders.
神经突的形成是影响生物体认知能力的一个重要过程。神经突的生长需要添加新的膜，但对于为膜扩张提供脂质所需的代谢重塑知之甚少。在这里，我们表明，突触活动是神经突生长的最重要诱导因素之一，它转录调节神经元葡萄糖转运体 Glut3 和糖酵解限速酶的表达，从而增强葡萄糖摄取和代谢，部分用于脂质合成。在机制上，CREB 调节 Glut3 和 Siah2 的表达，后者和 LDH 活性促进 HIF-1α 的低氧稳定，调节糖酵解限速基因的表达。显性负性 HIF-1α 的表达或 Glut3 的敲低会阻止活性依赖性神经突生长，而糖酵解的药理学抑制和早期 postnatal 小鼠中 HIF-1α 的特异性消融会损害神经突结构。这些结果表明，操纵神经元葡萄糖代谢可用于治疗一些脑发育障碍。
