Journal Article (Review Article)

DZNE-2020-07671

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein.

Lang, F. (Corresponding author) ; Pelzl, L. ; Schöls, L.DZNE* ; Hermann, A.DZNE* ; Föller, M. ; Schäffer, T. E. ; Stournaras, C.

2017
Karger Basel

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Please use a persistent id in citations: doi:10.1159/000485457

Abstract: 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.

Keyword(s): Animals (MeSH) ; Autophagy: physiology (MeSH) ; Cytoskeleton: metabolism (MeSH) ; Erythrocytes: metabolism (MeSH) ; Humans (MeSH) ; Neuroacanthocytosis: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Vesicular Transport Proteins: metabolism (MeSH) ; VPS13A protein, human ; Vesicular Transport Proteins

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. 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 ; National-Konsortium ; SCOPUS

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