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

Pelzl, Lisann; Hauser, Stefan; Elsir, Bhaeldin; Sukkar, Basma; Sahu, Itishri; Singh, Yogesh; Höflinger, Philip; Bissinger, Rosi; Jèmaà, Mohamed; Stournaras, Christos; Schöls, Lüdger; Läng, Florian

doi:10.1038/s41598-017-06451-1

Cited by 29 publications

(50 citation statements)

References 60 publications

(62 reference statements)

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“…[Ca 2+ ] i could be enhanced by Ca 2+ release from intracellular stores with subsequent stimulation of the Ca 2+ release activated Ca 2+ channel subunits ORAI1, ORAI2 and/or ORAI3 [56] by the Ca 2+ sensing proteins STIM1 and/or STIM2 [12, 57-59]. Upon stimulation with STIM1/2, the ORAI isoforms accomplish store-operated Ca 2+ entry (SOCE).…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

“…Along those lines, studies in Saccharomyces cerevisiae, Dictyostelium discoideum, Tetrahymena thermophila and Drosophila melanogaster point to the involvement of Vps13 proteins in cytoskeleton organization, vesicular trafficking, autophagy, phagocytosis, endocytosis, proteostasis, sporulation and mitochondrial function [38]. Chorein may support activation of phosphoinositide-3-kinase (PI3K)-p85-subunit [12, 39, 40] with subsequent increase of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation [39]. Phosphoproteomics of tyrosine phosphorylation in erythrocytes from ChAc patients pointed to altered function of the kinases FYN, ABL1, EGFR, FGFR1, IGF1R, TEC, TGFBR1 and BTK, as well as of the phosphatases PTPRC and ACP1 [41].…”

Section: Introductionmentioning

confidence: 99%

“…It has been speculated that chorein deficiency may foster the development of Alzheimer´s disease [26-28]. ChAc results in severe disability and early death of the affected patients [12]. Genetic knockout of chorein in mice leads to erythrocyte shape changes [24], neuronal apoptosis [29] and altered behavior [29].…”

Section: Introductionmentioning

confidence: 99%

“…ChAc is a rare differential of Huntington’s disease with a complex motor phenotype including generalized choreatic hyperkinesia, a peculiar feeding dystonia with tongue protrusion and tongue as well as lip biting, dysarthria, dysphagia, gait impairment with trunk instability due to sudden, violent spasms of the trunk, progressive distal muscle wasting and weakness, as well as increased plasma levels of creatine kinase [10-21]. The patients suffer in addition from epileptic seizures, cognitive impairment, and behavioral changes, such as obsessive-compulsive disorder [10, 12, 18, 22-25]. It has been speculated that chorein deficiency may foster the development of Alzheimer´s disease [26-28].…”

Section: Introductionmentioning

confidence: 99%

“…Chorein participates in the regulation of diverse functions [33, 34], including cytoskeletal architecture [33-35], exocytosis [12, 34, 36] and cell survival [12, 37]. …”

Section: Introductionmentioning

confidence: 99%

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Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

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Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca²⁺-channel accomplishing store operated Ca²⁺-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.

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Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Chorein participates in the regulation of diverse functions [33, 34], including cytoskeletal architecture [33-35], exocytosis [12, 34, 36] and cell survival [12, 37]. …”

Section: Introductionmentioning

confidence: 99%

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