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Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis.

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.
AuthorsMichael 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
JournalFASEB 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
PMID22227296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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