Abstract |
Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss-of-function mutations of the gene encoding vacuolar protein sorting-associated protein 13A (VPS13A) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea-acanthocytosis remains enigmatic. Here we show decreased phosphoinositide-3-kinase (PI3K)-p85-subunit phosphorylation, ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea-acanthocytosis and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1, or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells, both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2-associated protein, promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation, and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival, thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis.
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Authors | Michael Föller, Andreas Hermann, Shuchen Gu, Ioana Alesutan, Syed M Qadri, Oliver Borst, Eva-Maria Schmidt, Franziska Schiele, Jennifer Müller vom Hagen, Carsten Saft, Ludger Schöls, Holger Lerche, Christos Stournaras, Alexander Storch, Florian Lang |
Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 26
Issue 4
Pg. 1526-34
(Apr 2012)
ISSN: 1530-6860 [Electronic] United States |
PMID | 22227296
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Actins
- VPS13A protein, human
- Vesicular Transport Proteins
- bcl-Associated Death Protein
- Phosphatidylinositol 3-Kinases
- PAK1 protein, human
- p21-Activated Kinases
- rac1 GTP-Binding Protein
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Topics |
- Acanthocytes
(cytology, metabolism)
- Actins
(metabolism)
- Adult
- Aged
- Animals
- Apoptosis
(physiology)
- Erythrocytes
(cytology, metabolism)
- Female
- Gene Silencing
- Humans
- K562 Cells
- Male
- Middle Aged
- Mutation
- Neuroacanthocytosis
(genetics, pathology, physiopathology)
- Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Vesicular Transport Proteins
(genetics, metabolism)
- Young Adult
- bcl-Associated Death Protein
(genetics, metabolism)
- p21-Activated Kinases
(genetics, metabolism)
- rac1 GTP-Binding Protein
(genetics, metabolism)
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