Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca$^2$$^+$ signaling and dysregulated cell metabolism

Velebit Marković, Jelena (avtor), Horvat, Anemari (avtor), Smolič, Tina (avtor), Prpar Mihevc, Sonja (avtor), Rogelj, Boris (avtor), Zorec, Robert (avtor), Vardjan, Nina (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: astrocytes, cell metabolism, neurons
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: 18 str.
• Številčenje: Vol. 10, art. 6003
• PID: 20.500.12556/RUL-128779
• UDK: 616-092
• ISSN pri članku: 2045-2322
• DOI: 10.1038/s41598-020-62864-5
• COBISS.SI-ID: 34773465
• Datum objave v RUL: 28.07.2021

Gradivo je del revije

• Naslov: Scientific reports
• Skrajšan naslov: Sci. rep.
• Založnik: Nature Publishing Group
• ISSN: 2045-2322
• COBISS.SI-ID: 18727432

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 07.04.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: astrociti, celična presnova, nevroni