Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis Academic Article uri icon

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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.

authors

  • Föller, Michael
  • Hermann, Andreas
  • Gu, Shuchen
  • Alesutan, Ioana
  • Qadri, Syed
  • Borst, Oliver
  • Schmidt, Eva-Maria
  • Schiele, Franziska
  • Müller vom Hagen, Jennifer
  • Saft, Carsten
  • Schöls, Ludger
  • Lerche, Holger
  • Stournaras, Christos
  • Storch, Alexander
  • Lang, Florian

publication date

  • April 2012

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