Journal Article

DZNE-2020-05906

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients.

Pelzl, L. ; Elsir, B. ; Sahu, I. ; Bissinger, R. ; Singh, Y. ; Sukkar, B. ; Honisch, S. ; Schöls, L.DZNE* ; Jemaà, M. ; Lang, E. ; Storch, A.DZNE* ; Hermann, A.DZNE* ; Stournaras, C. ; Lang, F. (Corresponding author)

2017
Karger Basel

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Please use a persistent id in citations: doi:10.1159/000479901

Abstract: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment.Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry.SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 µM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB.In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment.

Keyword(s): Apoptosis: drug effects (MeSH) ; Boron Compounds: pharmacology (MeSH) ; Calcium: metabolism (MeSH) ; Calcium Release Activated Calcium Channels: antagonists & inhibitors (MeSH) ; Calcium Release Activated Calcium Channels: metabolism (MeSH) ; Calcium-Transporting ATPases: metabolism (MeSH) ; Case-Control Studies (MeSH) ; Cell Survival: drug effects (MeSH) ; Cells, Cultured (MeSH) ; Down-Regulation: drug effects (MeSH) ; Fibroblasts: cytology (MeSH) ; Fibroblasts: drug effects (MeSH) ; Fibroblasts: metabolism (MeSH) ; Fura-2: chemistry (MeSH) ; Heterocyclic Compounds, 3-Ring: pharmacology (MeSH) ; Humans (MeSH) ; Lithium: pharmacology (MeSH) ; Microscopy, Fluorescence (MeSH) ; Neuroacanthocytosis: metabolism (MeSH) ; Neuroacanthocytosis: pathology (MeSH) ; Boron Compounds ; Calcium Release Activated Calcium Channels ; Heterocyclic Compounds, 3-Ring ; thapsitranstagin ; Lithium ; 2-aminoethoxydiphenyl borate ; Calcium-Transporting ATPases ; Calcium ; Fura-2

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Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Non-Motor Symptoms in Parkinson's disease (AG Storch)
3. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2017

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Database coverage:
; ; ; ; DOAJ Seal ; Ebsco Academic Search ; National-Konsortium ; SCOPUS

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