20.500.12556/RUL-128779 Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca$^2$$^+$ signaling and dysregulated cell metabolism Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca$^2$$^+$ 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$^2$$^+$ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β$_2$-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. astrocytes cell metabolism neurons astrociti celična presnova nevroni true false true Angleški jezik Slovenski jezik Članek v reviji 2021-07-28 15:33:26 2021-07-28 15:33:29 2022-09-07 04:17:09 0000-00-00 00:00:00 2020 0 0 18 str. Vol. 10, art. 6003 Apr. 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-092 2045-2322 10.1038/s41598-020-62864-5 34773465 RAZ_Velebit_Markovic_Jelena_2020.pdf RAZ_Velebit_Markovic_Jelena_2020.pdf 1 2D352B8ACDE02811BCFAA5890F010F30 5e9e002d51004e4fa8f3157bbe439f1cc78b69f1a65a73813502e4204b013a2a 39f78825-efa8-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=145654 https://www.nature.com/articles/s41598-020-62864-5 0 0f5a2290-efa9-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=145655 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0