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Neurosignals. 2017;25(1):117-126. doi: 10.1159/000485457. Epub 2017 Nov 28.

Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein.

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Department of Physiology I, University of Tuebingen, Tübingen, Germany.
Department of Molecular Medicine II, Heinrich Heine University Duesseldorf, Düsseldorf, Germany.
Department of Internal Medicine III, University of Tuebingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases, Research site Tuebingen, Tübingen, Germany.
Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tübingen, Germany.
Department of Neurology and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden & DZNE, German Center for Neurodegenerative Diseases, Research Site Dresden, Dresden, Germany.
Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, Halle, Germany.
Institute of Applied Physics, University of Tuebingen, Tübingen, Germany.
Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.


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.


Apoptosis; Autophagy; Chorea-acanthocytosis; Cytoskeleton; Exocytosis; Lithium; Orai1; SGK1; Store operated Ca2+ entry

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