Laboratory of Cell Engineering, Celica Biomedical, 1000, Ljubljana, Slovenia.
Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia.
Sci Rep. 2020 Apr 7;10(1):6003. doi: 10.1038/s41598-020-62864-5.
Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD.
大多数肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）病例的神经元和非神经元细胞（包括为神经元提供营养代谢支持的星形胶质细胞）中均存在 TAR DNA 结合蛋白 43（TDP-43）的细胞质包含物。神经元的代谢主要依赖于去甲肾上腺素能系统的激活以释放去甲肾上腺素。去甲肾上腺素激活星形胶质细胞肾上腺素能受体可触发环磷酸腺苷（cAMP）和钙信号，并增强有氧糖酵解，生成乳酸，这是神经元的重要能量燃料。含有细胞质 TDP-43 包含物的星形胶质细胞可导致运动神经元死亡，但是否 TDP-43 包含物星形胶质细胞中的星形胶质细胞代谢和神经元代谢支持发生改变尚不清楚。我们使用荧光染料或遗传编码纳米传感器测量表达 TDP-43 包含物形成的 C 端片段或野生型 TDP-43 的星形胶质细胞中的脂滴和葡萄糖代谢。与表达野生型 TDP-43 的星形胶质细胞相比，含有 TDP-43 包含物的星形胶质细胞中的脂滴积累增加了 3 倍，表明脂滴代谢发生改变。在这些细胞中，去甲肾上腺素触发的细胞内 cAMP 和 Ca 水平增加分别减少了 35％和 31％，这可能是由于β肾上腺素能受体下调所致。尽管去甲肾上腺素在有和没有 TDP-43 包含物的星形胶质细胞中均触发了类似的细胞内乳酸水平增加，但在含有 TDP-43 包含物的星形胶质细胞中，有氧糖酵解的激活概率增加了 1.6 倍，并且乳酸 MCT1 转运体下调。因此，尽管在含有 TDP-43 包含物的星形胶质细胞中去甲肾上腺素能信号降低，但有氧糖酵解和脂滴积累却得到促进，这表明 TDP-43 相关 ALS 和 FTD 中星形胶质细胞代谢和神经元代谢支持失调。
