Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis

Autor: Itishri Sahu, Lisann Pelzl, Mohamed Jemaà, Philip Höflinger, Rosi Bissinger, Ludger Schöls, Christos Stournaras, Florian Lang, Bhaeldin Elsir, Yogesh Singh, Basma Sukkar, Stefan Hauser
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
ORAI1 Protein
Lithium (medication)
Stimulation
STIM1 protein
human
Benzoates
0302 clinical medicine
metabolism [Neuroacanthocytosis]
pathology [Neurons]
metabolism [Calcium]
genetics [ORAI1 Protein]
ORAI1 protein
human
Multidisciplinary
Cell Death
ORAI1
Kinase
Cell Differentiation
metabolism [Stromal Interaction Molecule 1]
STIM1
Healthy Volunteers
Neoplasm Proteins
Blot
metabolism [Neurons]
metabolism [ORAI1 Protein]
metabolism [Neoplasm Proteins]
030220 oncology & carcinogenesis
GSK 650394
Medicine
pathology [Fibroblasts]
metabolism [Fibroblasts]
Glucocorticoid
pharmacology [Benzoates]
medicine.drug
medicine.medical_specialty
Science
drug effects [Apoptosis]
Lithium
Biology
03 medical and health sciences
pharmacology [Bridged Bicyclo Compounds
Heterocyclic]
genetics [Stromal Interaction Molecule 1]
Internal medicine
medicine
Humans
drug effects [Neurons]
Stromal Interaction Molecule 1
drug effects [Fibroblasts]
genetics [Neoplasm Proteins]
pharmacology [Lithium]
Bridged Bicyclo Compounds
Heterocyclic
030104 developmental biology
Endocrinology
Apoptosis
Calcium
ddc:600
pathology [Neuroacanthocytosis]
Zdroj: Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
Scientific reports 7(1), 6457 (2017). doi:10.1038/s41598-017-06451-1
ISSN: 2045-2322
DOI: 10.1038/s41598-017-06451-1
Popis: Chorea-Acanthocytosis (ChAc), a neurodegenerative disorder, results from loss-of-function-mutations of chorein-encoding gene VPS13A. In tumour cells chorein up-regulates ORAI1, a Ca2+-channel accomplishing store operated Ca2+-entry (SOCE) upon stimulation by STIM1. Furthermore SOCE could be up-regulated by lithium. The present study explored whether SOCE impacts on neuron apoptosis. Cortical neurons were differentiated from induced pluripotent stem cells generated from fibroblasts of ChAc patients and healthy volunteers. ORAI1 and STIM1 transcript levels and protein abundance were estimated from qRT-PCR and Western blotting, respectively, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, as well as apoptosis from annexin-V-binding and propidium-iodide uptake determined by flow cytometry. As a result, ORAI1 and STIM1 transcript levels and protein abundance and SOCE were significantly smaller and the percentage apoptotic cells significantly higher in ChAc neurons than in control neurons. Lithium treatment (2 mM, 24 hours) increased significantly ORAI1 and STIM1 transcript levels and protein abundance, an effect reversed by inhibition of Serum & Glucocorticoid inducible Kinase 1. ORAI1 blocker 2-APB (50 µM, 24 hours) significantly decreased SOCE, markedly increased apoptosis and abrogated the anti-apoptotic effect of lithium. In conclusion, enhanced neuronal apoptosis in ChAc at least partially results from decreased ORAI1 expression and SOCE, which could be reversed by lithium treatment.
Databáze: OpenAIRE
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