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

Abstract 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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lisann Pelzl, Stefan Hauser, Bhaeldin Elsir, Basma Sukkar, Itishri Sahu, Yogesh Singh, Philip Höflinger, Rosi Bissinger, Mohamed Jemaà, Christos Stournaras, Ludger Schöls, Florian Lang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/34fec634c07e43438b1686562183e2b0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:34fec634c07e43438b1686562183e2b0
record_format	dspace
spelling	oai:doaj.org-article:34fec634c07e43438b1686562183e2b02021-12-02T16:06:55ZLithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis10.1038/s41598-017-06451-12045-2322https://doaj.org/article/34fec634c07e43438b1686562183e2b02017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06451-1https://doaj.org/toc/2045-2322Abstract 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.Lisann PelzlStefan HauserBhaeldin ElsirBasma SukkarItishri SahuYogesh SinghPhilip HöflingerRosi BissingerMohamed JemaàChristos StournarasLudger SchölsFlorian LangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lisann Pelzl Stefan Hauser Bhaeldin Elsir Basma Sukkar Itishri Sahu Yogesh Singh Philip Höflinger Rosi Bissinger Mohamed Jemaà Christos Stournaras Ludger Schöls Florian Lang Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
description	Abstract 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.
format	article
author	Lisann Pelzl Stefan Hauser Bhaeldin Elsir Basma Sukkar Itishri Sahu Yogesh Singh Philip Höflinger Rosi Bissinger Mohamed Jemaà Christos Stournaras Ludger Schöls Florian Lang
author_facet	Lisann Pelzl Stefan Hauser Bhaeldin Elsir Basma Sukkar Itishri Sahu Yogesh Singh Philip Höflinger Rosi Bissinger Mohamed Jemaà Christos Stournaras Ludger Schöls Florian Lang
author_sort	Lisann Pelzl
title	Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
title_short	Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
title_full	Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
title_fullStr	Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
title_full_unstemmed	Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis
title_sort	lithium sensitive orai1 expression, store operated ca2+ entry and suicidal death of neurons in chorea-acanthocytosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/34fec634c07e43438b1686562183e2b0
work_keys_str_mv	AT lisannpelzl lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT stefanhauser lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT bhaeldinelsir lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT basmasukkar lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT itishrisahu lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT yogeshsingh lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT philiphoflinger lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT rosibissinger lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT mohamedjemaa lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT christosstournaras lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT ludgerschols lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis AT florianlang lithiumsensitiveorai1expressionstoreoperatedca2entryandsuicidaldeathofneuronsinchoreaacanthocytosis
_version_	1718384768442171392

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

Ejemplares similares