Decreased Na+/K+ ATPase Expression and Depolarized Cell Membrane in Neurons Differentiated from Chorea-Acanthocytosis Patients

Autor: Zohreh Hosseinzadeh, Stefanie Schuster, Yogesh Singh, Nefeli Zacharopoulou, Philip Höflinger, Ludger Schöls, Christos Stournaras, Florian Lang, Lisann Pelzl, Yamini Sharma, Stefan Hauser, Eberhart Zrenner, Daniel Rathbun
Jazyk: angličtina
Rok vydání: 2020
Předmět:
medicine.medical_specialty
Programmed cell death
Patch-Clamp Techniques
Lithium (medication)
genetics [Sodium-Potassium-Exchanging ATPase]
lcsh:Medicine
metabolism [Cell Membrane]
Ouabain
Cell membrane
pharmacology [Bridged Bicyclo Compounds
Heterocyclic]
genetics [Vesicular Transport Proteins]
metabolism [Neuroacanthocytosis]
Internal medicine
metabolism [Vesicular Transport Proteins]
medicine
Humans
drug effects [Neurons]
pathology [Neurons]
metabolism [Sodium-Potassium-Exchanging ATPase]
Patch clamp
Na+/K+-ATPase
lcsh:Science
Cells
Cultured
antagonists & inhibitors [Protein Serine-Threonine Kinases]
Membrane potential
Multidisciplinary
pharmacology [Lithium]
Chemistry
lcsh:R
drug effects [Membrane Potentials]
Cell Differentiation
cytology [Induced Pluripotent Stem Cells]
pathology [Cell Membrane]
medicine.anatomical_structure
Endocrinology
antagonists & inhibitors [Immediate-Early Proteins]
metabolism [Neurons]
Case-Control Studies
cytology [Neurons]
SGK1
drug effects [Cell Membrane]
lcsh:Q
ddc:600
pharmacology [Benzoates]
pathology [Neuroacanthocytosis]
medicine.drug
Zdroj: Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
Scientific reports 10(1), 8391 (2020). doi:10.1038/s41598-020-64845-0
ISSN: 2045-2322
DOI: 10.1038/s41598-020-64845-0
Popis: Loss of function mutations of the chorein-encoding gene VPS13A lead to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with accelerated suicidal neuronal cell death, which could be reversed by lithium. Chorein upregulates the serum and glucocorticoid inducible kinase SGK1. Targets of SGK1 include the Na+/K+-ATPase, a pump required for cell survival. To explore whether chorein-deficiency affects Na+/K+ pump capacity, cortical neurons were differentiated from iPSCs generated from fibroblasts of ChAc patients and healthy volunteers. Na+/K+ pump capacity was estimated from K+-induced whole cell outward current (pump capacity). As a result, the pump capacity was completely abolished in the presence of Na+/K+ pump-inhibitor ouabain (100 µM), was significantly smaller in ChAc neurons than in control neurons, and was significantly increased in ChAc neurons by lithium treatment (24 hours 2 mM). The effect of lithium was reversed by SGK1-inhibitor GSK650394 (24 h 10 µM). Transmembrane potential (Vm) was significantly less negative in ChAc neurons than in control neurons, and was significantly increased in ChAc neurons by lithium treatment (2 mM, 24 hours). The effect of lithium on Vm was virtually abrogated by ouabain. Na+/K+ α1-subunit transcript levels and protein abundance were significantly lower in ChAc neurons than in control neurons, an effect reversed by lithium treatment (2 mM, 24 hours). In conclusion, consequences of chorein deficiency in ChAc include impaired Na+/K+ pump capacity.
Databáze: OpenAIRE
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