Effects of LPS analysed in mouse models harboring disease-mutations in the ±2- or ±3Na+/K+-ATPase, respectively

• Grant number: 16/21343-1
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): January 04, 2017
• Effective date (End): November 30, 2017
• Field of knowledge: Biological Sciences - Biochemistry
• Principal researcher: Cristoforo Scavone
• Grantee: Jacqueline Alves Leite
• Supervisor abroad: Karin Lykke-Hartmann
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Aarhus University, Denmark
• Associated to the scholarship: 14/10171-0 - Study of the molecular effect of OUA treatment on the HPA axis of rats exposed to chronic unpredictable stress, BP.DR

Abstract

The enzyme Na+,K+-ATPase (Sodium Potassium Adenosine Trisfosfatase) is an integral membrane ion pump, essential to maintain the osmotic balance of cells, by its energy-driven ability to export Na+ and import K+. Its functions are vital to all cells. Of the four ±1-4 subunit isoforms, ±1-3 are expressed in the central nervous system. The ±2 isoform is highly enriched in atrocytes and the ±3 isoform is neuron-specific. Mutations in the genes encoding ±2 and ±3 isoforms can cause different neurological disorders, such as familial hemiplegic migraine type-2 (FHM2) (ATP1A2 mutations), or Rapid-onset Dystonia pakinsonims and Alternating Hemiplegia of Childhood (RDP/AHC, repesctively, for a3 mutations). Interestingly, recent findings showed that knockdown of the a2Na+/K+-ATPase in mutant superoxide dismutase 1 (SOD1) astrocytes were able to protect motor neurons from degeneration in co-cultured primary motor neurons, and showed that mitochondrial respiration and inflammatory gene expressions were induced in astrocytes from the SOD1 mutant mice, suggesting that the upregulation of the a2Na+/K+-ATPase stimulated mRNAs encoding mitochondrial respiration and expression of secreted inflammatory factors. Moreover, previous studies showed that ouabain, an inhibitor of the Na+,K+-ATPase, presented an important anti-inflammatory and anti-apoptotic action in the brain. The overall goal of this project is to test the effect of Na+,K+-ATPase in neuroinflammation. Towards this purpose, we will use heterozygous mice harboring disease mutations in the a2 (a2+/G301R mice) and a3 (a3+/D801Y mice) isoforms, respectively. Lipopolysaccharide (LPS) is a major bacterial TLR4 ligand that activates the innate immune response, and systemic administration of LPS can cause neuroinflammation in animal models by mechanisms involving expression of pro-inflammatory cytokines, activation of NF-ºB and inhibition of neurotrophic factor production. Accumulating evidence suggests a relationship between neurodegenerative diseases and neuroinflammation. For this purpose, we propose to examine how ±2 and ±3-containing Na+,K+-ATPase are associated with neuroinflammation in a2+/G301R and a3+/D801Y mice. Therefore, the project is important as it will contribute to a better understanding of the pathophysiology of the diseases associated with neuroinflammaiton.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LEITE, J. A.; ISAKSEN, T. J.; HEUCK, A.; SCAVONE, C.; LYKKE-HARTMANN, K.. The alpha(2) Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation. SCIENTIFIC REPORTS, v. 10, n. 1, AUG 25 2020. (16/07427-8, 16/21343-1, 14/10171-0)